| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Staphylococcus aureus Bacteremia Including Infective Endocarditis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Complicated S. aureus bacteremia and SA-RIE.(right-sided infective endocarditis caused by Staphylococcus. Aureus) |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004035 |
| E.1.2 | Term | Bacterial infection due to staphylococcus aureus |
| E.1.2 | System Organ Class | 100000004862 |
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| 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 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) |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of telavancin compared with standard intravenous therapy in the treatment of S. aureus bacteremia including SA-RIE
- To evaluate the PK profiles of telavancin and vancomycin in subjects with S. aureus bacteraemia, including SA-RIE |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 within 48 hours before randomisation, referred to as the 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 CB, 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) known bacteraemia with at least one of the following risk factors for CB[25-28].
• Any venous catheter considered to be the source of the infection, demonstrated by inflammation or purulent drainage from the catheter insertion site AND evidence of catheter-associated thrombosis upon removal. NOTE: A peripheral venous catheter with just inflammation or purulent drainage from the catheter insertion site without evidence of thrombus is not consistent with CB.
• A central venous catheter (CVC) considered to be the source of infection, demonstrated by inflammation or purulent drainage from the CVC insertion site or presence of thrombus on ultrasound
• A long-term intravascular catheter (eg, tunneled cuffed intravascular catheter or subcutaneous port catheter), considered to be the source of infection, demonstrated by inflammation or purulent drainage from the catheter insertion site or presence of thrombus on ultrasound
• New onset cardiac murmur consistent with tricuspid regurgitation
• 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 laboratory), 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 partner. Male subjects must agree to use medically acceptable birth control for at least one month following last dose of study medication. A vasectomy or a condom used with a spermicide is a medically acceptable birth control method for males.
10. Considered likely to comply with the study procedures and to return for scheduled evaluations
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|
| E.4 | Principal exclusion criteria |
1. Treatment with any potentially effective (anti-staphylococcal) systemic antibiotic for more than 60 hours within 7 days before randomization (preferable to have no more than 48 hours)
EXCEPTION: Documented resistance to the prior systemic antibacterial therapy, confirmed by a microbiological laboratory report
2. Requirement or anticipated requirement of non-study systemic antibiotics during the study
3. Presence of an infection source (eg, intravascular line, abscess, septic arthritis, infected prosthetic material, wound) that will not be managed or controlled (eg, removal or replacement of the infected line, drainage of abscess, aspiration or drainage of septic arthritis, removal or replacement of infected prosthesis, or debridement of infected 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 LIE at enrolment, according to Modified Duke Criteria (App. 1). Right-sided infective endocarditis (RIE) is permitted. If the subject is diagnosed with LIE after enrollment, subject will be allowed to remain on study.
6. At the time of enrolment known or highly suspected osteomyelitis, meningitis or metastatic septic foci involving the CNS. 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, meningitis, or metastatic septic foci in the CNS.
7. Known at the time of enrolment to have MRSA bacteremia that is non susceptible to daptomycin AND has a vancomycin MIC >2 mcg/mL
8. Confirmed evidence (identification or Gram stain) of a mixed polymicrobial infection with a Gram-negative pathogen that requires non-study antibiotic treatment with agent(s) that have activity against Gram-negative pathogens
9. Previous participation in an anti-infective study during the past 12 months
10. A history of significant hypersensitivity, 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 may require exclusion. If the pathogen is known MSSA, allergy to both PCN/cephalosporin and daptomycin may require exclusion. Investigator discretion is advised on a case-by-case basis.
11. Solid organ transplantation or bone marrow transplantation within 6 months before randomization
12. Severe neutropenia, defined as an absolute neutrophil count (ANC) <500 cells per microliter, or expected development of severe neutropenia during study
13. Known or suspected human immunodeficiency (HIV) infection with a CD4+ T-cell count <200/μL within the previous 6 months.
14. Subjects requiring concomitant administration of anti-coagulation therapy (eg, intravenous heparin sodium) AND requiring specific coagulation testing known to have interference by telavancin (prothrombin time/international normalized ratio, activated partial thromboplastin time, or activated clotting time, or coagulation-based Factor X activity assay). Although telavancin does not interfere with coagulation, it interferes with some assays used to monitor coagulation. The use of unfractionated heparin and low molecular weight heparin AND testing using an Anti-Xa chromogenic testing assay would be permissible.
15. Severe liver disease, ie, Child-Pugh Class C (App. 2), or AST or ALT more than 10 times the upper limit of normal (ULN)
16. Requirement for acute renal replacement therapy; or acute kidney injury (AKI) defined as an acute decrease in CrCl to < 30 mL/min and at least one of the following:
≥2x increase in serum Cr or 50% decrease in glomerular filtration rate (GFR) within the 2 weeks prior to enrollment (RIFLE stage 2 injury (Appendix 3)
oliguria defined as urine output <0.5 mL/kg per hour for ≥12 hours at any time during screening
Chronic renal insufficiency with a stable CrCl <30 mL/min, including chronic hemodialysis, is permitted
17. Shock or hypotension (supine systolic blood pressure <80 mm Hg) unresponsive to fluids or pressors within 24 hours prior to randomization
18. QTc >460 msec (using either the Bazett or Fridericia formula), congenital long QT syndrome, uncompensated or new onset heart failure, , aortic stenosis, aortic insufficiency, or mitral insufficiency
19. Serum creatine kinase (CK) ≥2000 U/L
20. Breast-feeding or pregnant or intending to become pregnant (self or partner) at any time during the study
21. Any other condition that in the opinion of the investigator would jeopardize the safety or rights of a subject or would render the subject unable to comply with the protocol; or any other condition that in the opinion of the investigator may confound the data
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
This study will evaluate:
1. Efficacy : Clinical outcome (success or failure) for subjects with CB or RIE in the mAT population
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. At TOC visit (either 38 (+/-2) days or 52 (+/- 2) days after randomization, depending on the classification of the infection type) in the mAT population. |
|
| E.5.2 | Secondary end point(s) |
1. Efficacy:
• Clinical outcome (success or failure) in the mAT and ME populations
• Clinical response (success or failure) in the mAT and ME populations
• Development of new metastatic foci of S. aureus infection after Day 8 in the mAT and ME populations
•Duration of treatment with study medication by baseline clinical diagnosis in the mAT and ME populations
• For subjects with a positive S. aureus blood culture on Day 1, time to all blood cultures negative for S. aureus for two days in succession (i.e., clearance of bacteremia) (does not have to be consecutive calendar days) in the mAT and ME populations; date will be first of the two days in succession.
•28-day all-cause mortality for subjects with a baseline diagnosis of CB or RIE in the mAT and ME populations
•Incidence of AEs, treatment-emergent AEs, SAEs, and deaths in the safety population
•Incidence of key laboratory indices in the safety population
Evaluation of signs and symptoms consistent with S. aureus infection such as: Blood cultures, physical examination, and echocardiography (TEE, or TTE if TEE is not possible); and may also include, but not limited to, chest X-ray, additional specimen cultures, ultrasonography, bone scan, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scan.
2.Safety:
Adverse Events
Clinical laboratory results
Vital signs
Use of concomitant medication
Physical examination
3. Pharmacokinetic, From approximately 124 subjects randomized to receive telavancin. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Screening to ToC
2. Screening to ToC
3. Day 1: At 1 hour, between 4 to 8 hours, and D2: priot to the start of the infusion (within 30 minutes before dosing)
Days 3, 5: Predose
Day 7: Predose , and between 4 to 8 hours after the start of the infusion.
Day 14: Predose
For each televancin dose change: predose, between 1-4 hours after start of infusion and on the next day prior to the start of the next infusion (within 30 minutes before dosing) |
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| 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 | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Brazil |
| Colombia |
| Israel |
| Mexico |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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