| 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 | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10046571 |
| E.1.2 | Term | Urinary tract infection |
| 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 objective is to demonstrate that eravacycline is non-inferior to ertapenem in microbiological outcome in the microbiological modified intent-to-treat (micro-MITT) and microbiologically evaluable (ME) populations at the Test of Cure (TOC) visit.
For the FDA: The primary objective is to demonstrate that IV eravacycline is non-inferior to ertapenem in responder outcome (clinical cure and microbiologic success) in the microbiological intent-to-treat (micro-ITT) population at the End of IV (EOI) visit (within 1 day of the completion of IV study drug treatment) and Test of Cure (TOC) visit (defined as 14-17 days after randomization).
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
1. To compare responder outcomes in the treatment arms at Day 5.
2. To compare clinical outcomes in the treatment arms at Day 5, EOI, End of Treatment (EOT), TOC, and Follow-up (FU) visits.
3. To compare microbiologic outcomes in the treatment arms at Day 5, EOI, EOT, TOC and FU visits.
4. To assess safety and tolerability of IV eravacycline administration.
5. To explore pharmacokinetic (PK) parameters of IV 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 (e.g., 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 30 days (placing of stents or catheters is not considered to be surgical modification)
2. At least 18 years of age at time of consent
3. Able to provide informed consent. For subjects with diminished decision-making capacity and where applicable law permits, a Legally Authorized Representative may consent on behalf of a prospective subject to the subject's participation.
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 > 100.4°F / 38°C) or hypothermia
(oral, rectal, tympanic, or by temporal artery temperature < 95°F /
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. ≥ 10 white blood cells (WBCs) per cubic millimeter, OR
c. ≥ 10 WBCs per high power field
6. 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 (e.g., condom) during the study and for 14 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 (refer to section 11.4.1 for definition of nonchildbearing 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 14 days following last study drug dose,
OR
c. Sexual abstinence |
|
| E.4 | Principal exclusion criteria |
1. Use of systemic antibiotics effective in cUTI within 72 hours prior
torandomization EXCEPT under the following circumstances:
a. Subjects with suspected acute cUTI who have received a single dose of effective non-study antibiotics for the acute cUTI
b. Signs and symptoms of cUTI developed while on the antibiotic for another indication
2. History of an ertapenem-resistant urinary tract infection within 1 year
of consent
3. Likely to require > 10 days of antibiotic treatment to cure the acute cUTI or likely to receive ongoing antibacterial drug prophylaxis prior to the FU visit (eg. Subjects with chronic vesiculo-ureteral reflux).
4. Unlikely to survive at least through the duration of the study
5. Hypotension, systolic blood pressure ≤ 90 mmHg
6. 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 catheters or obtain diagnosis)
7. Known or suspected urinary fungal infection
8. Uncomplicated lower urinary tract infections
9. Suspected or confirmed active prostatitis, or currently under treatment for prostatitis
10. High risk for cUTI due to Pseudomonas sp. (eg, history of prior cUTIs due to Pseudomonas, ≥ 20 mg QD prednisone or equivalent steroid, and other risk factors as perceived by the Investigator)
11. History of renal transplantation
12. Presence of an ileal loop
13. Any history of trauma to the pelvis or urinary tract occurring within 30 days prior to consent
14. Indwelling urinary catheters present at screening which are not expected to be removed or replaced within 72 hours of randomization (eg, nephrostomy tubes, stents, urethral and suprapubic catheters).
15. Known concomitant HIV infection with CD4 counts below 200 cells/μL within six months prior to consent, or an AIDS defining diagnosis within six months prior to consent
16. Neutropenia (ANC < 1,000 PMNs/μL)
17. Participation in a study with an experimental drug or device within 30 days prior to consent
18. Known or suspected hypersensitivity to tetracyclines, carbapenems, or β-lactams
19. History of seizures
20. Any other unstable or clinically significant concurrent medical condition (e.g., immunosuppressive therapy, chemotherapy, class IV heart or lung disease, end stage renal disease, or requiring hemodialysis) 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) |
The primary endpoint will be the microbiologic outcome at the TOC visit in the micro-MITT and ME populations.
For the FDA: the primary endpoints of the study are the responder rates (clinical cure and microbiologic success) at the End of IV (EOI) and Test of Cure (TOC) visits in the micro-ITT population.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of IV (EOI) and Test of Cure (TOC) visits |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of the study are
- Responder rate at Day 5
- Clinical outcome at Day 5, End of IV (EOI), EOT (End of Treatment), Test of Cure (TOC), and Follow-Up (FU)
- Microbiologic outcome at Day 5, EOI, EOT, TOC, and FU |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 5, End of IV (EOI), EOT (End of Treatment), Test of Cure (TOC), and Follow-Up (FU) |
|
| 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 | 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| 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 |
| Austria |
| Bulgaria |
| Estonia |
| Georgia |
| Hungary |
| Latvia |
| Moldova, Republic of |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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