| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Hematogenous Osteomyelitis Due to Gram-Positive Organisms |
|
| E.1.1.1 | Medical condition in easily understood language |
| Bacterial infection and inflammation of the bone or bone marrow |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009081 |
| E.1.2 | Term | Chronic osteomyelitis |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046076 |
| E.1.2 | Term | Unspecified osteomyelitis |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009091 |
| E.1.2 | Term | Chronic osteomyelitis, site unspecified |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 demonstrate the noninferiority of daptomycin compared with vancomycin or nafcillin (or β-lactam equivalent) in pediatric subjects with AHO with respect to improvement in the general categories of Pain, Inflammation, and Limb Function on or before Study Day 5 in the MITT Analysis Set. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of the Sponsor drug versus comparator in pediatric subjects with AHO
• To evaluate the safety and tolerability of daptomycin versus comparator in pediatric subjects with AHO
• To evaluate the pharmacokinetics of daptomycin in pediatric subjects with AHO |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed consent in writing from parent(s) or legally-acceptable representative(s) and, informed assent from subject (if age appropriate according to local requirements)
2. Male or female, 1 year to < 18 years old (subject must be randomized before 18th birthday)
3. Presence of AHO warranting hospitalization and IV antibacterial therapy
4. Presence of AHO meeting each of the following criteria (I, II, and III):
I. Acute onset or worsening within the 10 days before randomization of at least 2 of the following 7 clinical symptom parameters (organized into 3 general categories) such that at least 1 category will be present and if only 1 category is present it needs to be of at least moderate severity.
• Pain
○ Localized pain
○ Point tenderness (on palpation)
• Inflammation
○ Localized warmth in the affected area
○ Localized swelling in the affected area
○ Area of induration
• Limb Function
○ Difficulty bearing weight on affected limb
○ Motion restriction and/or loss of function in affected limb
AND
II. At least 1 of the following:
• Radiologic imaging (magnetic resonance imaging [MRI], bone scan, x-ray, or computed tomography [CT] scan) consistent with osteomyelitis performed within 7 days before randomization (or planned to occur within 7 days after randomization). If a qualifying radiologic imaging study is inconclusive, follow-up radiologic imaging must be done to confirm the diagnosis of AHO.
OR
• A positive microbiological culture from a bone biopsy or bone aspirate (if available), or blood, or presumptive evidence of gram-positive infection by Gram-stain of specimen, or positive PCR (or other rapid detection method) testing.
AND
III. Presence of at least 1 of the following:
• CRP > 10 mg/dL
• Erythrocyte sedimentation rate (ESR) > 20 mm/hour
• Leukocytosis (> 12,000 white blood cells [WBC]/mm3), leukopenia (< 4000 WBC/mm3), or immature neutrophils [bands] (> 10% regardless of total peripheral WBC)
• Fever > 38°C (100.4ºF) or hypothermia < 36°C (96.8ºF)
5. Female subjects who have reached menarche must have a negative serum or urine pregnancy test
6. Female subjects who have reached menarche and are sexually active must be willing to practice sexual abstinence or dual methods of birth control (eg, condom or diaphragm with spermicidal foam or gel) during treatment and for at least 28 days after the last dose of IV study drug (if no PO switch) or PO therapy |
|
| E.4 | Principal exclusion criteria |
1. Documented history of any hypersensitivity or allergic reaction to daptomycin, vancomycin, or any β-lactam antibacterial agent
2. Diagnosis of contiguous septic arthritis associated with AHO at baseline
3. AHO of the spine or pelvis or AHO involving multiple locations (2 or more bones)
4. Chronic osteomyelitis or symptoms of osteomyelitis exceeding 14 days
5. Major trauma, penetrating trauma (including a puncture wound of the foot), postoperative osteomyelitis, foreign body in or adjacent to affected bone or joint, or other iatrogenic bone or joint infections present at the site of infection
6. AHO due to a proven gram-negative organism
7. At risk for infection with gram-negative organisms (e.g. with enteric gram-negative organisms due to recent gastrointestinal surgery or complex urinary tract anatomy).
8. Presence of transient tenosynovitis, juvenile rheumatoid arthritis (JRA), reactive arthritis, bony tumors, and other osteoarticular diseases suspected to be due to a nonbacterial (eg, fungal or mycobacterial) etiology
9. More than 24 hours of any potentially effective IV antibacterial therapy for AHO within 96 hours before randomization. Exceptions: a) microbiological or clinical treatment failure with a nonstudy IV antibacterial therapy that was administered for at least 48 hours. Failure must be confirmed by either microbiological laboratory report or documented worsening or no improvement of clinical signs or symptoms; b) low-dose tetracycline derivative for acne (eg, doxycycline 50 mg q12h); c) Prior treatment with oral antibiotics if subject has worsening or no improvement of clinical signs and symptoms
10. Requirement for any potentially effective concomitant systemic antibacterial therapy for gram-positive infections
11. History of seizures, with the exception of well-documented febrile seizure of childhood; peripheral neuropathy
12. History of rhabdomyolysis (with the exception of muscle injury due to trauma)
13. Sickle cell anemia
14. Subjects in whom clinical assessments of AHO (eg, localized pain, point tenderness, localized warmth, localized swelling, induration, difficulty bearing weight, motion restriction and/or loss of function) may not be possible (eg, due to a surgical procedure resulting in non-removable cast or splint placement) during the first several days post randomization
15. Any condition (eg, cystic fibrosis, current septic shock) that would make the subject, in the opinion of the Investigator, unsuitable for the study (eg, would place a subject at risk or compromise the quality of the data), or evidence of immediately life-threatening disease, progressively fatal disease, or life expectancy of 6 months or less
16. Creatinine clearance (CrCl) < 50 mL/min/1.73 m2 as calculated using the updated Schwartz “bedside” formula:
CrCl (mL/min/1.73 m2) = 0.413 × height (length) (cm) / serum creatinine (mg/dL)
17. Evidence of significant hepatic, hematologic, or immunologic dysfunction as defined by the following:
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper limit of normal (× ULN) or bilirubin level > 2 × ULN
• Neutropenia (< 500 neutrophils/mm3)
• Thrombocytopenia (< 50,000 platelets/mm3)
• If human immunodeficiency virus (HIV) positive, CD4 count < 200 cells/mm3 at the last measurement, history of AIDS-defining illness within the last year, or at risk for HIV if child is < 18 months of age
• Bone marrow or solid organ recipients who have had an episode of graft versus host disease or acute rejection episode, respectively, within the last 6 months; and/or bone marrow ablative therapy, including bone marrow transplantation, within the last 12 months
• Diagnosis of any primary immunodeficiency disorders
18. Creatine kinase (CK) elevation ≥ 10 × ULN (upper limit of normal) without symptoms or ≥ 5 × ULN with symptoms
19. Suspected or confirmed pneumonia
20. Females who are currently pregnant or breastfeeding
21. Participation in any study involving administration of an investigational agent or device within 30 days before the start of first dose of IV study drug or previously participated in the current study or in another study of daptomycin (in which an active agent was received)
22. Unable or unwilling to adhere to the study-specified procedures and restrictions |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy measure is clinical improvement in the general categories of Pain, Inflammation, and Limb Function on or before Study Day 5 in the MITT Analysis Set.
The determination of clinical improvement will be based on the Investigator’s overall assessment of severity of each of the symptom categories. Based on this evaluation, a subject will be considered to have met criteria for clinical improvement according to the following definition:
• If 3 general categories are present at baseline: at least a 1-point improvement (ie, severe to moderate, moderate to mild, mild to absent) in at least 2 of the general categories and no worsening in the other
• If 2 general categories are present at baseline: at least a 2-point improvement (ie, severe to mild, moderate to absent) in at least 1 of the general categories and no worsening or new findings in the others OR at least a 1-point improvement in both and no new findings in the other
• If 1 general category is present at baseline: at least a 2-point improvement (ie, severe to mild, moderate to absent) in that category and no new findings in the others |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
• Composite endpoint of clinical improvement in the general categories (Pain, Inflammation, and Limb Function), body temperature ≤ 38°C (100.4°F) over the preceding 24 hours, and CRP decreased by at least 30% from baseline on or before Study Day 5 (confirmed with a follow-up CRP within 4 to 7 days) in the MITT Analysis Set
• Clinical outcome by subject at EOIV, EOT, and TOC in the MITT and CE analysis sets
• Clinical outcome by baseline pathogen at TOC in the mMITT and ME analysis sets
• Microbiological outcome by subject at TOC in the mMITT and ME analysis sets
• Microbiological outcome by baseline pathogen at TOC in the mMITT and ME analysis sets
• Sustained clinical improvement at EOT and TOC in the MITT Analysis Set
Safety:
Safety evaluations will be conducted in the Safety Analysis Set and assessments will include:
• Adverse events (AEs): AEs, serious adverse events (SAEs), deaths, and discontinuations due to AEs
• Clinical: vital signs (pulse, blood pressure, respiratory rate, temperature) and focused neurological examinations
• Laboratory: complete blood count with differential and chemistry panel
Pharmacokinetics:
Pharmacokinetic (PK) outcome measures will include plasma concentrations of daptomycin |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| EOIV (if on IV study drug) or EOT (if on PO therapy) |
|
| 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 | 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Standard of care; vancomycin or nafcillin |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 35 |
| 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 |
| France |
| Germany |
| Greece |
| Guatemala |
| Hungary |
| Israel |
| Italy |
| Korea, Democratic People's Republic of |
| Peru |
| Romania |
| Spain |
| Turkey |
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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