| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of subjects undergoing surgical standard of care for osteomyelitis associated with an infected prosthetic hip or knee joint caused by methicillin-resistant Staphylococcus Aureus and/or coagulase-negative Staphylococci. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064250 |
| E.1.2 | Term | Staphylococcal osteomyelitis |
|
| 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 evaluate the safety parameter of CPK levels >500 in PJI subjects treated with daptomycin at 6mg/kg or 8mg/kg versus comparator (vancomycin or teicoplanin) |
|
| E.2.2 | Secondary objectives of the trial |
Safety: To evaluate the safety parameters, including vital signs, laboratory analytes and adverse events in subjects treated with daptomycin at 6 mg/kg and 8 mg/kg versus those treated with comparator
Clinical Efficacy: To evaluate the clinical efficacy of daptomycin at 6 mg/kg and 8 mg/kg versus comparator at the TOC visit
Microbiological Response: To evaluate the microbiological response rate of daptomycin at 6 mg/kg and 8 mg/kg versus comparator at the TOC visit
Pharmacokinetics: To assess the PK of daptomycin at 6 mg/kg versus 8 mg/kg
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Informed consent has been obtained;
2.Between the ages of 18 and 80, inclusive;
3.Subject must have a diagnosis of PJI in a hip or knee joint which has never previously been totally revised because of an infection and for which they are anticipated to undergo a two-stage replacement surgery;
4.Has one of the following microbiological identifiers of PJI:
a. Two confirmatory deep intra-operative cultures obtained at Surgery #1 from 4 or more independent surgical sites for staphylococci (e.g. S. aureus or CoNS); or
b. One culture positive for staphylococci (e.g. S. aureus or CoNS) from affected joint synovial fluid aspirate obtained within 6 weeks (42 days) prior to Surgery #1 with a confirmatory positive culture from 1 or more deep intra-operative surgical sites within 72 hours of Surgery #1; or
c. In the event intra-operative cultures are negative or remain pending after 72 hours, a patient may be considered for study participation if 2 Gram stains show Gram-positive pathogens or histopathological evidence of staphylococci is obtained within 72 hours following Surgery #1; or
d. Two positive blood cultures for staphylococci (e.g. S. aureus or CoNS) obtained from two independent peripheral sites within 48 hours prior to Surgery #1.
5.Subject, if female of childbearing potential, must be willing to practice reliable birth control measures (e.g., condoms or diaphragms together with a spermicidal foam or gel) during study treatment and for at least 28 days after completion of study medication and has a documented negative pregnancy test result within 72 hours prior to study medication administration
6.Subject must be willing to participate in the study, follow protocol study treatment regimen, and comply with all planned assessments.
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| E.4 | Principal exclusion criteria |
1.Subject is anticipated to have retention of the infected prosthetic joint, a one-stage prosthetic joint replacement procedure, or resection of the prosthetic joint and arthrodesis;
2.Subject has undergone a total revision for previous infection of the joint under study;
3. Subject has permanent intravascular prosthetic material in a site or sites other than the joint under study, includingsuch as heart valves, or pacemakers, and any other metalwork or prosthetic implant unless deemed acceptable by the Medical Monitor;
4.Subject is likely to require non-study systemic antibiotics effective against staphylococci for any other reason during the trial period from first dose of study medication through discharge from the hospital following Surgery #2;
5.Subject is anticipated to require oral antibiotic step-down or suppressive antibiotic therapy after EOT and through discharge from the hospital following Surgery #2;
6.Subject has a Creatinine Clearance <30 mL/min as determined by the Cockcroft-Gault equation using actual body weight;[Note: If CRCL drops below 30 mL/min while on treatment the Medical Monitor must be contacted. A decision will be made between the Medical Monitor and the Investigator on a case-by-case basis whether to discontinue a patient from the study.];
7.Subject has a significant hepatic dysfunction (AST/ALT ≥5 x ULN or total bilirubin ≥3.0mg/dL);
8.Subject is unable to discontinue HMG CoA reductase inhibitor therapy from randomization through the EOT visit;
9.Subject has a mixed Gram-positive and Gram-negative PJI or a pure Gram-negative PJI;
10. Subject has a mixed Gram-positive PJI other than staphylococci;
11. Cultures positive for staphylococci that have a non-susceptible MIC to daptomycin, vancomycin or teicoplanin;
12. Subject has a fungal or mycobacterial PJI;
13. Subject is known to be HIV-infected with CD4 count ≤200 cells/ mm3;
14. Subject has an abnormal CPK (elevated CPK level ≥2 x ULN) at baseline as measured by central laboratory;
15. Subject is currently under treatment with chemotherapeutic agents, excluding chronic maintenance therapy (e.g. tamoxifen to prevent relapse of primary breast cancer);
16. Subject is severely neutropenic (absolute neutrophil count <0.500x103/µL);
17. Subject has been previously enrolled in the study;
18. Subject has a documented history of significant allergy or intolerance to daptomycin, vancomycin, teicoplanin, or semi-synthetic penicillins;
19. Subject has pneumonia;
20. Subject has prior exposure to daptomycin (either investigational or commercial) within the past 30 days;
21. Subject is currently receiving another investigational drug;
22. Subject is pregnant, nursing, or lactating;
23. Subject is receiving or is expected to receive chronic immunosuppressive therapy during the study. Corticosteroids at doses greater than 10 mg daily for longer than 8 weeks duration will be considered immunosuppressive.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for the study is the incidence of elevated CPK (defined as any CPK value above 500 U/L based on central laboratory assessments) in the CPK safety population at any time point from Day 3 of study medication through 7 days following the last dose of study drug (Day 7P). These data will be analyzed as a dichotomous variable: “No CPK > 500U/L” versus “Any CPK >500U/L”. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 7 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 9 |
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