Clinical Trial to evaluate the safety and tolerability of telavancin comparedwith standard intravenous therapy in the treatment of S. aureusbacteremia

Phase 1

Conditions: Staphylococcus aureus Bacteremia Including Infective Endocarditis
MedDRA version: 20.0Level: LLTClassification code 10004035Term: Bacterial infection due to staphylococcus aureusSystem Organ Class: 100000004862
Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Registration Number: EUCTR2014-004372-27-IT

Lead Sponsor: THERAVANCE BIOPHARMA ANTIBIOTICS, INC.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 248

Inclusion Criteria

1. Male or female at least 18 years old at the time of consent
2. Subject has signed an informed consent form. If a subject is unable
to give consent, when legally permitted, consent must be obtained from
the subject's legally acceptable representative.
NOTE: Subject, or appropriate legal representative, must be able to
communicate effectively with investigator and site staff
3. At least one blood culture positive for S. aureus obtained within 48
hours before randomization, referred to as the qualifying blood culture
(QBC)
4. In addition to the QBC, subject must have at least one of the
following signs or symptoms of bacteremia:
• Temperature = 38.0°C
• White blood cell (WBC) count > 10,000 or < 4,000 cells/µL, or > 10%
immature neutrophils (bands) regardless of total peripheral WBC count
• Tachycardia (heart rate > 90 bpm)
• Tachypnea (respiratory rate >20 breaths/min)
• Hypotension (systolic blood pressure <90 mmHg)
• Signs and symptoms of localized catheter-related infection
(tenderness and/or pain, erythema, swelling, purulent exudate within 2
cm of entry site)
5. Subject must, at enrollment, have either 1) known right-sided
infective endocarditis by Modified Duke's Criteria, 2) known complicated
bacteremia, demonstrated as signs or symptoms of metastatic foci of S.
aureus infection (eg, any infection remote from the primary focus caused
by hematogenous seeding or extension of infection beyond the primary
focus), or 3) at least one of the following risk factors for complicated
bacteremia [25-28].
• A central venous catheter (CVC) in the internal jugular or subclavian
vein (Note: peripheral venous catheters are not sufficient for
enrollment)
• Any CVC considered to be the source of the infection, demonstrated
by inflammation or purulent drainage from the CVC insertion site
• Presence of a long-term intravascular catheter (eg, tunneled cuffed
intravascular catheter or subcutaneous port catheter); must be removed
within 3 days after enrollment
• New or diastolic cardiac murmur
• Community onset bacteremia (eg, subject does not live in a
healthcare facility)
• Pathogen known to be MRSA at enrollment
• Duration of symptoms =2 days at time of presentation (prior to start
of antibiotic therapy)
• Skin exam findings suggesting acute systemic infection (ie, petechiae,
vasculitis, infarcts, ecchymoses or pustules due to the infection)
6. Willing to receive intravenous antibiotics for the duration of
treatment
7. Expected survival of at least 3 months
8. Female subjects must be non-pregnant and non-lactating. If a female
subject is of childbearing potential, must have a documented negative
pregnancy test at screening
NOTE: All females are considered to be of childbearing potential unless
they are postmenopausal (amenorrheic for at least 2 years) or
documented to be surgically sterile (bilateral tubal ligation or total
hysterectomy). A subject may be admitted to the study on the basis of a
negative urine pregnancy test (local lab), pending the result of the
serum pregnancy test.
9. If sexually active, must agree to use a highly effective method of
birth control with partners of childbearing potential during the study and
for 1 month after study drug dosing
NOTE: A highly effective method of birth control is defined as one that
results in a low failure rate (ie, < 1% per year) when used consistently
and correctly, such as implants, injectables, combined oral
contraceptives, some intra-uterine devices (IUDs), sexual abstinence, or
a vasectomized

Exclusion Criteria

1. Treatment with any potentially effective (anti-staphylococcal)
systemic antibiotic for more than 48 hours within 7 days before
randomization
EXCEPTION: Documented resistance to the prior systemic antibacterial
therapy, confirmed by a microbiological laboratory report (pathogens
non susceptible to telavancin, or non-susceptible to daptomycin and a
vancomycin MIC >1 mcg/mL are not permitted)
2. Requirement or anticipated requirement of potentially effective
(anti-staphylococcal) non-study systemic antibiotics during the study
3. Presence of an infection source (eg, intravascular line, abscess,
infected prosthetic material, wound) that will not be managed or
controlled (eg, removal of line, drainage of abscess, removal of infected
prosthesis, or debridement of wound) within the first 3 days of study
drug treatment
4. Presence of prosthetic cardiac valve or cardiac device (eg,
implantable cardioverter defibrillator [ICD]), permanent pacemaker, or
cardiac valve support ring)
5. Known or suspected left-sided infective endocarditis (LIE), according
to Modified Duke Criteria (Appendix 1)
NOTE: Right-sided infective endocarditis (RIE) is permitted
6. Known or suspected osteomyelitis or meningitis
NOTE: Investigators should use clinical judgment to determine whether
additional imaging studies (eg, X-ray, computed tomography scan,
magnetic resonance imaging) are indicated at screening to rule out the
presence of osteomyelitis
NOTE: Evidence of metastatic complications related to the primary
infection such as right-sided endocarditis, septic arthritis, septic
pulmonary emboli are permitted. S. aureus pneumonia is permitted
7. Prior episode of invasive S. aureus infection (defined as having
resolved after appropriate follow-up per discretion of the investigator)
within the past 30 days
8. Infecting pathogen with confirmed (prior to enrollment) nonsusceptibility
to telavancin; or confirmed non susceptibility to
daptomycin and a vancomycin MIC >1 mcg/mL; or a mixed polymicrobial
infection with a Gram-negative pathogen with confirmed resistance to
aztreonam
9. Subjects with HIV/AIDS requiring prophylactic
trimethoprim/sulfamethoxazole are excluded (or requiring potentially
effective concomitant administration of agents containing cyclodextrin
(eg, itraconazole, voriconazole)
10. Previous participation in an anti-infective study during the past 12
months
11. A history of significant allergy or intolerance to telavancin; caution
should be taken in subjects with a history of severe hypersensitivity
reaction to vancomycin. If the pathogen is known MRSA, allergy to both
vancomycin and daptomycin. If the pathogen is known MSSA, allergy to
both anti-staphylococcal PCN/cephalosporin and daptomycin
12. Solid organ transplantation or bone marrow transplantation within
6 months before randomization
13. Severe neutropenia, defined as an absolute neutrophil count (ANC)
<500 cells per microliter, or expected development of severe
neutropenia during study
14. Known or suspected human immunodeficiency (HIV) infection with
a CD4+ T-cell count <100/µL within the previous 6 months
NOTE: Subjects with HIV/AIDS requiring prophylactic
trimethoprim/sulfamethoxazole are excluded (or requiring potentially
effective (anti-staphylococcal) non-study systemic antibiotics during the
study).
15. Severe liver disease, ie, Child-Pugh Class C (Appendix 2), or
aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
more than 10 times the upper limit of normal (ULN)
16. Re

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To compare telavancin to standard intravenous therapy (ie, vancomycin,<br>daptomycin, anti-staphylococcal penicillin, or cefazolin) clinical<br>outcomes in the treatment of S. aureus bacteremia including S. aureus<br>right-sided infective endocarditis (SA-RIE);Secondary Objective: - To evaluate the incidence of new metastatic foci of S. aureus infection<br>after Day 8<br>- To evaluate the safety and tolerability of telavancin compared with<br>standard intravenous therapy in the treatment of S. aureus bacteremia<br>including SA-RIE;Primary end point(s): Efficacy : Clinical outcome (success or failure);Timepoint(s) of evaluation of this end point: At TOC visit (either 56 (+/-2) days or 70 (+/- 2) days after randomization, depending on the classification of the infection type) in the mITT analysis set.

Secondary Outcome Measures

Name	Time	Method

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