Efficacy and Safety Study of Eravacycline Compared With Levofloxacin in Complicated Urinary Tract Infections

• Register: EUCTR
• Last refreshed on: 10 October 2016
• Main ID: EUCTR2013-004556-38-DE
• Date of registration: 23/12/2013
• Prospective Registration: Yes
• Primary sponsor: Tetraphase Pharmaceuticals, Inc.
• Public title: Efficacy and Safety Study of Eravacycline Compared With Levofloxacin in Complicated Urinary Tract Infections
• Scientific title: A Phase 3, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy and Safety of Eravacycline Compared with Levofloxacin in Complicated Urinary Tract Infections - IGNITE2
• Date of first enrolment: 22/04/2014
• Target sample size: 973
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-004556-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Double-dummy If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Brazil, Bulgaria, Canada, Colombia, Czech Republic, Estonia, Georgia, Germany, Greece, Hungary, Israel, Italy, Korea, Republic of, Latvia, Mexico, Moldova, Republic of, Peru, Poland, Romania, Russian Federation, South Africa, Thailand, Ukraine, United States

Contacts

• Name: Clinical Operation Department
• Affiliation: PSI CRO Deutschland GmbH

• Name: Clinical Operation Department
• Affiliation: PSI CRO Deutschland GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male and female subjects with either:
a. Pyelonephritis and normal urinary tract anatomy (approximately 30% 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 CHF or volume related) such that the serum 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 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, OR
b. At least 10 white blood cells per cubic millimeter, OR
> 10 white blood cells cells 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 (> 10,000 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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 876
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 97

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)
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, = 20mg 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])
16. Presence or possible signs of significant hepatic disease:
a. Alanine aminotransferase or aspartate aminotransferase > 3 x ULN OR
b. Total bilirubin > 3 x ULN OR
c. Alkaline phosphatase > 3 x ULN, OR
d. Subjects with diagnosis of hepatic failure
17. Participation in a study with an experimental drug within 30 days
18. Known or suspected hypersensitivity to tetracyclines or fluoroquinolones
19. 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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Complicated urinary tract Infections
MedDRA version: 18.0 Level: LLT Classification code 10046576 Term: Urinary tract infection, site not specified System Organ Class: 100000004862

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Intervention(s)

Product Name: eravacycline
Product Code: TP-434
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: ERAVACYCLINE
CAS Number: 1207283-85-9
Current Sponsor code: TP-434
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 53-

Product Name: eravacycline
Product Code: TP-434
Pharmaceutical Form: Capsule
INN or Proposed INN: ERAVACYCLINE
CAS Number: 1207283-85-9
Current Sponsor code: TP-434
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: eravacycline
Product Code: TP-434
Pharmaceutical Form: Capsule
INN or Proposed INN: ERAVACYCLINE
CAS Number: 1207283-85-9
Current Sponsor code: TP-434
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 125-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Trade Name: Levofloxacin 5 mg/ml solution for infusion
Product Name: Levofloxacin
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: LEVOFLOXACIN
CAS Number: 100986-85-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-

Trade Name: Levofloxacin 250 mg Film-coated Tablets
Product Name: Levofloxacin
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: LEVOFLOXACIN
CAS Number: 100986-85-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: To compare clinical response for sbj in the treatment arms at Dose Cycle
3, End of IV Therapy (EOI), End of Therapy (EOT), PT, and Late Post-
Treatment (LPT) visits in the following populations: Intent-to-Treat
(ITT) population; Clinically evaluable (CE) population; Micro-ITT
population; Micro-MITT population; Microbiologically evaluable (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 erav administration in the safety
population.
To test for superiority of erav over levo in the treatment of cUTI: For
those sbj with infections caused by quinolone-resistant pathogens, erav
will be compared with levo in responder outcome in the micro-ITT
population at the PT visit.
To explore PK parameters of erav

Main Objective: 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).

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).

Timepoint(s) of evaluation of this end point: the Post-Treatment (PT) visit

Secondary Outcome(s)

Secondary end point(s): 1.To compare clinical response for subjects in the treatment arms at Dose Cycle 3, End of IV Therapy (EOI), End of Therapy (EOT), PT, and Late
Post-Treatment (LPT) visits in the following populations: Intent-to-Treat
(ITT) population; Clinically evaluable (CE) population; Micro-ITT
population; Micro-MITT population; Microbiologically evaluable (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
- Mirco-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.

Timepoint(s) of evaluation of this end point: Dose Cycle 3, EOI, EOT, PT, and LPT visits

Secondary ID(s)

NCT01978938

TP-434-010

2013-004556-38-HU

Source(s) of Monetary Support

Tetraphase Pharmaceuticals, Inc.