| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Hematogenous Osteomyelitis of the Long Bones Known or Suspected to be due to Gram-Positive Organisms |
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| E.1.1.1 | Medical condition in easily understood language |
| Infection of the long bone |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Microbiological Phenomena [G06] |
| MedDRA Classification |
| 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 clinical improvement at Day 8 of intravenous dalbavancin to that of the comparator regimen (either cefazolin, nafcillin, oxacillin or vancomycin) for the treatment of acute hematogenous osteomyelitis (AHOM) of the long bones known or suspected to be due to Gram-positive organisms in the modified ITT (mITT) population defined as all randomized subjects with a confirmed diagnosis of AHOM (clinical picture and radiologic or microbiologic findings consistent with AHOM), excluding subjects with confirmed culture of Gram-negative organisms from any baseline specimen. |
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| E.2.2 | Secondary objectives of the trial |
To compare clinical response of dalbavancin to the comparator regimen at Day 8 in the intent-to-treat (ITT) and Clinically Evaluable (CE) populations
To compare reduction in CRP relative to the highest value in the two treatment groups on Day 8, Day 28, Day 60 and Day 180 in the ITT, modified ITT (mITT) and CE populations
To compare clinical response at Day 28, Day 60 and Day 180 of dalbavancin to the comparator regimen in the mITT and CE populations
To compare clinical response by pathogen at Day 8, Day 28, Day 60 and Day 180 of dalbavancin to the comparator regimen in the microbiological mITT (micro-mITT) and microbiologically evaluable (ME) populations
To compare the safety and tolerability of dalbavancin to that of the comparator regimen in the safety population.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male or female subjects 2-16 years of age
A diagnosis of acute (< 2 weeks in duration) hematogenous osteomyelitis (AHOM) of the long bones (ulna, radius, femur or tibia) defined by the following (multiple sites of infection within long bones are allowed):
Limb abnormality manifested by one or more of the following: pain, point tenderness upon palpation, motion restriction, loss of function of the affected limb
Magnetic resonance imaging [MRI] consistent with AHOM (indistinctly marginated edema-like pattern of bone marrow hypointensity on unenhanced T1-weighted sequences, hyperintensity on fat-saturated T2-weighted and STIR sequences and/or abnormal enhancement on gadolinium-enhanced fat-saturated T2-weighted sequences, with or without visible periostitis or cortical bone destruction)
(OR)
Gram-positive cocci documented on a baseline Gram-stain from a bone specimen or from blood cultures.
Elevated CRP (low sensitivity)
A signed and dated written informed consent document indicating that the subject (or a legally acceptable representative or the subject’s parent(s)/legal guardian(s)) has been informed of all pertinent aspects of the trial. If required by the local IRB/IEC, assent of the older subjects will be obtained.
Subjects, and, if required by local/site regulations, their parent(s)/legal guardians(s), must be willing and able, if discharged from the hospital, to return to the hospital or a designated clinic for scheduled visits, treatment, laboratory tests and other outpatient procedures as required by the protocol.
Subjects must be expected to survive with appropriate antibiotic therapy and appropriate supportive care throughout the study.
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| E.4 | Principal exclusion criteria |
Treatment with an investigational drug within 30 days preceding the first dose of study medication.
Receipt of > 24 hours of potentially effective intravenous antibacterial therapy for AHOM within 96 hours before randomization, unless the pathogen isolated was documented to be MRSA that was resistant to the administered antibiotic.
Evidence of subacute or chronic osteomyelitis including: symptoms > 2 weeks in duration, sinus tract with/without purulent drainage, or radiographic evidence of periosteal reaction or sequestrum
AHOM of non-long bones (e.g., pelvis or spine)
Extraosseous findings such as: subperiosteal abscess, pyomyositis, venous thrombosis, or pulmonary embolism
Previous history of septic arthritis or osteomyelitis
Major trauma, open-fracture, puncture wound of the foot, post-operative osteomyelitis, foreign body in or adjacent to affected bone or joint, or other iatrogenic bone or joint infections present at the site of infection.
Septic arthritis that is non-contiguous to osteomyelitis, as diagnosed by isolation of a pathogen from synovial fluid culture
Immunosuppression/immune deficiency, including hematologic malignancy, recent bone marrow transplant (in post-transplant hospital stay), absolute neutrophil count < 500 cells/mm3, receiving immunosuppressant drugs after organ transplantation, receiving oral steroids (> 20 mg prednisolone per day or equivalent), chronic granulomatous disease, and known or suspected human immunodeficiency virus (HIV) infection with a CD4 cell count < 200 cells/mm3 or with a past or current acquired immunodeficiency syndrome (AIDS)-defining condition and unknown CD4 count.
Evidence of Gram-negative bacteria by gram stain in the absence of Gram-positive organisms; fungus or mycobacteria at baseline.
Gram-negative bacteremia, even in the presence of Gram-positive infection or Gram-positive bacteremia. Note: If a Gram-negative bacteremia develops during the study, or is subsequently found to have been present at Baseline, the patient should be removed from study treatment and receive appropriate antibiotic(s) to treat the Gram-negative bacteremia.
A history of oral ulcers preceding the onset of musculoskeletal findings, recent gastrointestinal surgery (within 2 months prior to study entry) or complex urinary tract anatomy
Infection due to an organism known prior to study entry to be not susceptible to dalbavancin (dalbavancin mean inhibitory concentration (MIC) > 0.12 µg/mL) or vancomycin (vancomycin MIC > 2 μg/mL).
Concomitant systemic antibacterial therapy for Gram-positive infections (eg, Rifampin, gentamicin).
Concomitant condition requiring any antibiotic therapy that would interfere with the assessment of study drug for the condition under study.
Sickle cell anemia
Cystic fibrosis
Known or suspected hypersensitivity to glycopeptide antibiotics.
Patients with a rapidly fatal illness, who are not expected to survive for 3 months.
Positive urine (or serum) pregnancy test at screening (post-menarchal females only) or after admission (prior to dosing).
Pregnant or nursing females; sexually active females of childbearing potential who are unwilling or unable to use adequate contraceptive precautions (female subjects to have pregnancy testing are those who are at least 10 years old with menarche and/or thelarche [beginning of breast development]).
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Unwilling or unable to follow study procedures
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Clinical improvement at Day 8 in the mITT population: improvement in subjective pain and/or point tenderness and/or range of motion or ability to bear weight
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
To compare clinical response of dalbavancin to the comparator regimen at Day 8 in the intent-to-treat (ITT) and Clinically Evaluable (CE) populations
To compare reduction in CRP relative to the highest value in the two treatment groups on Day 8, Day 28, Day 60 and Day 180 in the ITT, modified ITT (mITT) and CE populations
To compare clinical response at Day 28, Day 60 and Day 180 of dalbavancin to the comparator regimen in the mITT and CE populations
To compare clinical response by pathogen at Day 8, Day 28, Day 60 and Day 180 of dalbavancin to the comparator regimen in the microbiological mITT (micro-mITT) and microbiologically evaluable (ME) populations
To compare the safety and tolerability of dalbavancin to that of the comparator regimen in the safety population. |
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| E.5.2 | Secondary end point(s) |
Clinical response at Day 8 in the ITT and Clinically Evaluable (CE) populations
Reduction in CRP (percent reduction) relative to the highest value in the two treatment groups on Day 8, Day 28, Day 60 and Day 180 in the ITT, mITT and CE populations
Clinical response at Day 28, Day 60, and Day 180 in the mITT and CE populations
Clinical response by pathogen at Day 8, Day 28, Day 60 and Day 180 in the micro-mITT and ME populations
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| An interim analysis for sample size re-estimation will be performed when early clinical response data at Day 8 are available for approximately 60% of the patients (171 patients). |
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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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Vancomycin, cefazolin, nafcillin or oxacillin |
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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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Czech Republic |
| France |
| Germany |
| Italy |
| Romania |
| Russian Federation |
| Spain |
| 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
|
LVLS
End of Study in all participating countries is defined as the last patient’s Final Visit |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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