Clinical Trial to evaluate the safety and tolerability of telavancin compared with standard intravenous therapy in the treatment of S. aureus bacteremia

Phase 1

• Conditions: Staphylococcus aureus Bacteremia Including Infective Endocarditis; MedDRA version: 19.0Level: 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-HU
• Lead Sponsor: Theravance Biopharma Antibiotics, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2016-04-26
• Last Update Posted: 21 May 2018

Recruitment & Eligibility

• Status: ot Recruiting
• 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), s

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) non-susceptibility 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 limi

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, daptomycin, anti-staphylococcal penicillin, or cefazolin) clinical outcomes in the treatment of S. aureus bacteremia including S. aureus right-sided infective endocarditis (SA-RIE);Secondary Objective: - To evaluate the incidence of new metastatic foci of S. aureus infection after Day 8<br>- To evaluate the safety and tolerability of telavancin compared with standard intravenous therapy in the treatment of S. aureus bacteremia including SA-RIE;Primary end point(s): This study will evaluate: <br>1. Efficacy : Clinical outcome (success or failure) <br><br><br><br>;Timepoint(s) of evaluation of this end point: 1. 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.