E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bacteremia caused by Staphylococcus Aureus. |
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E.1.1.1 | Medical condition in easily understood language |
Presence of bacteria Staphylococcus Aureus in the blood stream. |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054637 |
E.1.2 | Term | Staphylococcal bacteremia |
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 assess the safety of intravenous (i.v.) daptomycin versus standard of care antibiotics in pediatric subjects aged 2-17 years of age with bacteremia. |
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E.2.2 | Secondary objectives of the trial |
• To compare the efficacy of i.v. daptomycin versus standard of care antibiotics in pediatric subjects aged 2-17 years of age with bacteremia caused by S. aureus; • To determine exposure by measuring plasma levels of daptomycin at pre-dose (trough) and end of infusion (Cmax) to explore exposure-response analyses in pediatric subjects aged 2-17 years of age with bacteremia. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written parental (or appropriate legal representative) informed consent prior to any study-related procedure not part of normal medical care; 2. Written subject assent (as appropriate); 3. Male or female between the ages of > 4 and 17 years of age inclusive, (ages > 2 years after eDMC approval); 4. If female, subject must not be pregnant, nursing, and is either: a. Not of childbearing potential, defined as pre-menarche or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or b. If of childbearing potential: either abstaining from sexual intercourse or practicing a barrier method of birth control (e.g., a diaphragm or contraceptive sponge) along with 1 of the following methods: oral or parenteral contraceptives. Subjects must be willing to practice these methods for the duration of the trial and for at least 90 days after last dose of study medication; 5. Males are required to practice reliable birth control methods (abstinence, condom or other barrier device) during the conduct of the study and for at least 90 days after last dose of study medication unless sterilized; 6. Able to comply with the study procedures and to return for scheduled post-treatment evaluations; 7. Have proven or probable S. aureus bacteremia defined as follows: Proven • Proven infections will be considered those with S. aureus identified from at least one blood culture bottle by conventional culture methods or by a rapid diagnostic test obtained within 3 calendar days prior to the first dose of study medication (Day -3, Day –2 or Day –1) Probable • Probable infections will be those with a preliminary blood culture result demonstrating Gram-positive cocci in clusters upon Gram stain, suggestive of a staphylococcal infection. If the final blood culture yields coagulase negative staphylococci after the patient is enrolled, only high risk patients with persistent bacteremia documented by multiple cultures taken on separate days or from different sites yielding the same organism can continue on study therapy. Patients at high risk include, but are not limited to, immunocompromised children, cancer patients, or those with a potential source of infection from devices or i.v. catheters that are not intended to be removed. |
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E.4 | Principal exclusion criteria |
1. Previous systemic antimicrobial therapy effective against S. aureus exceeding 72 hours duration administered anytime during the 96 hours prior to the first dose of study drug; Exception: subject is eligible if culture data demonstrate in vitro resistance to prior i.v. antibiotic; 2. Is anticipated to require non-study systemic antibiotics that may be potentially effective against S. aureus; 3. Has shock or hypotension unresponsive to fluids or vasopressors for ≥4 hours; 4. Has received an investigational drug or participated in any experimental procedure within 30 days of randomization (Investigational use of approved products may be permitted with the approval of the Medical Monitor); 5. Has a documented history of significant allergy or intolerance to daptomycin; 6. Has renal insufficiency (i.e. estimated creatinine clearance rate (CLcr)<50 mL/min/1.73m2); 7. CPK elevation ≥ 10 X ULN (upper limit of normal) without symptoms or ≥ 5 X ULN with symptoms such as myalgia, muscle stiffness, muscle weakness; 8. Has history of clinically significant (as assessed by the Investigator) muscular disease, nervous system or seizure disorder, including unexplained muscular weakness, history of peripheral neuropathy, Guillain-Barré or spinal cord injury; previous uncomplicated febrile seizure allowed; 9. Has history of or current rhabdomyolysis; 10. Has suspected or confirmed S. aureus pneumonia (septic emboli in the lung is not an exclusion if clear evidence of source of infection is other than lungs) empyema, meningitis, or endocarditis;
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E.5 End points |
E.5.1 | Primary end point(s) |
Evaluation of Safety: The safety of daptomycin and SOC will be evaluated by monitoring adverse events (AEs), serious adverse events (SAEs), serum chemistry (including serum CPK level) and changes in physical and focused neurological and other laboratory examinations. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Focused neurological examinations will be done at baseline, while on i.v. study drug, at End-of-Therapy (EOT) and Test-of-Cure (TOC: 7-14 days after last dose of study medication). The focused neurological examinations will include assessments of sensation, pupillary reflex and tracking, peripheral reflexes (biceps, patellar tendon, ankle jerk and plantar response), muscle tone and strength (upper and lower limbs), coordination (finger to nose) and tremor of the hands/fingers. A questionnaire for motor developmental skills will be used at baseline and at the last follow-up contact (25-35 days after EOT). Safety will be assessed from the administration of the first dose of study medication through the last follow-up visit (25-35 days after last dose of study medication). |
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E.5.2 | Secondary end point(s) |
1).Evaluation of Exposure Response: Daptomycin exposure will be determined by measuring plasma levels at predose (trough) and end of infusion (Cmax) 2).Evaluation of Efficacy. 3).Microbiologic Response: The Subject’s Microbiological Response at EOT will be derived from the Pathogen-Level Microbiological Response at EOT for all of the subject’s Baseline Infecting Pathogens and from the presence or absence of a Superinfecting Pathogen (Gram-positive) at EOT. For each Baseline Infecting Pathogen, “Eradicated” will be considered a satisfactory response. For each Baseline Infecting Pathogen, “Documented Persistent” will be considered an unsatisfactory response. Microbiological success: • A subject for whom all baseline infecting pathogens were eradicated within 7 days from start of effective i.v. antibiotics for uncomplicated bacteremia with no source of infection present, and 10 days for complicated bacteremia; or • When source of infection is not removed and no superinfecting Gram-positive pathogen(s) were isolated on therapy, EOT, and TOC. Microbiological failure: • A subject with the persistence, presumed persistence or relapse of the baseline infecting pathogen after Day 7 from start of antibiotics to which the pathogen is sensitive when no ongoing source of infection is present or after Day 10 when the source of infection has not been removed; or • Presence of a superinfecting Gram-positive pathogen(s) in EOT or TOC blood cultures Overall success: This will be based on microbiologic response and clinical response at TOC (cure, improved, failure or nonevaluable) with regard to the Investigator’s determination of the resolution or improvement of signs and symptoms. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1).Evaluation of Exposure Response: between Days 3 and 5 of i.v. study drug treatment to explore exposureresponse analyses in all age groups. 2).Evaluation of Efficacy: Clinical efficacy will be based on Investigator’s assessment of clinical response at TOC (cure, improved, failure or non-evaluable) with respect to resolution or improvement of clinical signs and symptoms. 3).Microbiologic Response- please refer to point 3 of the section " Secondary end points"
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Exposure response parameters in the exposure response population. |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
stratified by age group; blinded evaluator |
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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 | Yes |
E.8.2.3.1 | Comparator description |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Australia |
Brazil |
Chile |
Colombia |
Greece |
Guatemala |
Hungary |
Italy |
Israel |
Panama |
Romania |
Ukraine |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 7 |