| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated urinary tract Infections |
|
| E.1.1.1 | Medical condition in easily understood language |
| Complicated urinary tract Infections |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046576 |
| E.1.2 | Term | Urinary tract infection, site not specified |
| 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 that eravacycline is non-inferior to levofloxacin in responder outcome (clinical and microbiological response vs failure) in the microbiological intent-to-treat micro-ITT population at the Post-Treatment (PT) visit (defined as 6-8 days after the completion of therapy). |
|
| E.2.2 | Secondary objectives of the trial |
•To compare clinical response for subjects in the treatment arms at Dose Cycle 3, EOI, EOT, PT, and LPT visits in the following populations:
-ITT population
-Clinically evaluable (CE)
-Micro-ITT
-Micro-MITT
-ME population
•To compare time to resolution of signs and symptoms by treatment group
•To compare microbiologic response in the treatment arms at Dose Cycle 3, EOI, EOT, PT, and LPT visits in the following populations:
-Micro-ITT population
-Micro-MITT population
-ME population
•To assess safety and tolerability of eravacycline administration in the safety population
•To test for superiority of eravacycline over levofloxacin in the treatment of cUTI:
-For subjects with infections caused by quinolone-resistant pathogens, eravacycline will be compared with levofloxacin in responder outcome in the micro-ITT population at the PT visit
•To explore pharmacokinetic (PK) parameters of eravacycline |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects with either:
a. Pyelonephritis and normal urinary tract anatomy (approximately 50% of the total population), OR
b. cUTI with at least one of the following conditions associated with a risk for developing cUTI:
i. Indwelling urinary catheter
ii. Urinary retention (at least approximately 100 mL of residual urine after voiding)
iii. History of neurogenic bladder
iv. Partial obstructive uropathy (eg, nephrolithiasis, bladder stones, and ureteral strictures)
v. Azotemia of renal origin (not congestive heart failure CHF or volume related) such that the serum blood urea nitrogen BUN is elevated (> 20 mg/dL) AND the serum BUN:creatinine ratio is < 15
vi. Surgically modified or abnormal urinary tract anatomy (eg, bladder diverticula, redundant urine collection system, etc.) EXCEPT urinary tract surgery within the last month (Placing of stents or catheters is not considered to be surgical modification)
2. At least 18 years of age
3. Able to provide informed consent
4. At least two of the following signs or symptoms:
a. Chills, rigors, or warmth associated with fever (oral, rectal, tympanic, or by temporal artery temperature > 38°C) or hypothermia (oral, rectal, tympanic, or by temporal artery temperature < 35°C)
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
5. Urine specimen with evidence of pyuria
a. Dipstick analysis positive for leukocyte esterase (where positive result is at least "++" as indicated on the urine dipstick provided in the laboratory kit), OR
b. At least 10 white blood cells (WBCs) per cubic millimeter, OR
≥ 10 white blood cells (WBCs) per high power field
6. The following subjects who have received previous/ongoing antibiotics will be eligible for enrollment:
a. Subjects with cUTI and a known baseline pathogen who have received prior antibiotic therapy for a minimum of 72 hours, but who are deemed clinical and microbiological failures (urine culture obtained after 72 hours of therapy with >10,000 colony-forming units [CFU]/mL)
b. Subjects with suspected acute cUTI who have received a single dose of effective non-study antibiotics for the acute cUTI in the previous 24 hours
7. Subjects must agree to use a highly reliable method of birth control
a. Male subjects must agree to use an effective barrier method of contraception during the study and for 30 days following the last dose if sexually active with a female of childbearing potential
b. Female subjects must not be pregnant or nursing. For females of childbearing potential, subjects must commit to either:
i. Use at least two medically accepted, effective methods of birth control (eg, condom, spermicidal gel, oral contraceptive, indwelling intrauterine device, hormonal implant /patch, injections, approved cervical ring, etc.) during study drug dosing and for 30 days following last study drug dose, OR
ii. Sexual abstinence |
|
| E.4 | Principal exclusion criteria |
1. Concurrent use of non-study antibacterial drug therapy that would have a potential effect on outcome evaluations in subjects with cUTI, including:
a. Subjects with a history of a levofloxacin-resistant urinary tract infection
b. Likely to receive ongoing antibacterial drug prophylaxis prior to the LPT visit (eg, subjects with vesiculo-ureteral reflux)
c. Use of systemic antibiotics effective in cUTI within 72 hours prior to enrollment except under circumstances meeting Inclusion Criterion 6
2. Likelihood that the subject will not survive at least through the duration of the study (approximately 4 weeks)
3. Hypotension, systolic blood pressure ≤ 90 mmHg
4. Complicated pyelonephritis with complete obstruction or known or suspected renal or perinephric abscess, emphysematous pyelonephritis, OR
Any condition likely to require surgery to achieve cure (this does NOT include procedure to place cathertors or obtain diagnosis)
5. Known or suspected urinary fungal infection
6. Uncomplicated lower urinary tract infections
7. Suspected or confirmed active prostatitis, or currently under treatment for prostatitis
8. Subjects with high risk for cUTI due to Pseudomonas sp. (eg, history of prior cUTIs due to Pseudomonas, ≥ QD prednisone or equivalent steroid, and other risk factors as perceived by the investigator)
9. History of renal transplantation
10. Presence of an ileal loop
11. Any history of trauma to the pelvis or urinary tract occuring within 30 days of screening
12. Indwelling urinary catheters present at screening expected to remain in place after IV therapy has been completed (eg,nephrostomy tubes, stents, urethral and suprapubic catheters)
13. Known concomitant HIV infection with CD4 counts below 200 cells/µL within the last six months, or an AIDS defining diagnosis within the last six months
14. Neutropenia (ANC < 1,000 PMNs/µL)
15. Creatinine clearance of < 50 mL/min as estimated by the Cockcroft-Gault equation (eCCr):
eCCr [mL/min]=((140-Age [yrs] ) × Body Weight [kg] × [0.85 if Female])/(72 × Serum Creatinine [mg⁄dL])
Note: The following exclusion criterion may be substituted for that based on Cockcroft-Gault to determine eligibility: glomerular filtration rate < 50 mL/min/1.73 m2 as estimated by the Modification of Diet in Renal Disease equation (eGFR)
16. Participation in a study with an experimental drug within 30 days
17. Known or suspected hypersensitivity to tetracyclines or fluoroquinolones
18. Any other unstable or clinically significant concurrent medical condition (ie, immunosuppressive therapy, chemotherapy, or class IV heart or lung disease) that would, in the opinion of the investigator, jeopardize the safety of a subject and/or their compliance with the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To demonstrate that eravacycline is non-inferior to levofloxacin in responder outcome (clinical and microbiological response vs failure) in the micro-ITT population at the Post-Treatment (PT) visit (defined as 6-8 days after the completion of therapy). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| the Post-Treatment (PT) visit |
|
| E.5.2 | Secondary end point(s) |
1.To compare clinical response for subjects in the treatment arms at Dose Cycle 3, EOI, EOT, PT, and LPT visits in the following populations:
- ITT population
- Clinically evaluable (CE) population
- Micro-ITT population
- Micro-MITT population
- ME population
2. To compare time to resolution of signs and symptoms by treatment group.
3. To compare microbiologic response in the treatment arms at Dose Cycle 3, EOI, EOT, PT and LPT visits in the following populations:
- Micro-ITT population
- Micro -MITT population
- ME population
4.To assess safety and tolerability of eravacycline administration in the safety population.
5. To test for superiority of eravacycline over levofloxacin in the treatment of cUTI:
- For those subjects with infections caused by quinolone-resistant pathogens, eravacycline will be compared with levofloxacin in responder outcome in the micro-ITT population at the PT visit.
6.To explore pharmacokinetic (PK) parameters of eravacycline. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Dose Cycle 3, EOI, EOT, PT, and LPT visits |
|
| 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 | 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| 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 |
| Argentina |
| Bulgaria |
| Chile |
| Colombia |
| Czech Republic |
| Estonia |
| Georgia |
| Germany |
| Greece |
| Hungary |
| India |
| Israel |
| Italy |
| Korea, Republic of |
| Latvia |
| Mexico |
| Moldova, Republic of |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| South Africa |
| Taiwan |
| Ukraine |
| United States |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
