Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Children, Known or Suspected to be Caused by Susceptible Gram-positive Organisms, Including MRSA

Study Overview
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Brief Summary
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To determine the safety and descriptive efficacy of dalbavancin for the treatment of acute bacterial skin and skin structure infections in children, aged birth to 17 years (inclusive), known or suspected to be caused by susceptible Gram-positive organisms, including methicillin-resistant strains of Staphylococcus aureus.

Official Title
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A Phase 3, Multicenter, Open-Label, Randomized, Comparator Controlled Trial of the Safety and Efficacy of Dalbavancin Versus Active Comparator in Pediatric Subjects With Acute Bacterial Skin and Skin Structure Infections

Conditions
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Methicillin-Resistant Staphylococcus Aureus, Bacterial Infections, Staphylococcal Skin Infections

Intervention / Treatment
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* Drug: Dalbavancin single dose
* Drug: Dalbavancin two dose
* Drug: Comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients birth to 17 years (inclusive) A clinical picture compatible with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) suspected or confirmed to be caused by Gram-positive bacteria, including Methicillin-resistant Staphylococcus aureus (MRSA). In addition to local signs of ABSSSI, the patient has at least one of the following: Fever, defined as body temperature ≥ 38.4°C (101.2°F) taken orally, ≥ 38.7°C (101.6°F) tympanically, or ≥ 39°C (102.2°F) rectally (core temperature) OR Leukocytosis (WBC > 10,000 mm3) or leukopenia (WBC < 2,000 mm3) or left shift of >10% band neutrophils Infection either involving deeper soft tissue or requiring significant surgical intervention Major cutaneous abscess characterized as a collection of pus within the dermis or deeper that is accompanied by erythema, edema and/or induration which i. requires surgical incision and drainage, and ii. is associated with cellulitis such that the total affected area involves at least 35 cm2 of erythema, or total affected area of erythema is at least BSA (m2) x 43.0 (cm2/m2), OR iii. alternatively, involves the central face and is associated with an area of erythema of at least 15 cm2 b. Surgical site or traumatic wound infection characterized by purulent drainage with surrounding erythema, edema and/or induration which occurred within 30 days after the trauma or surgery and is associated with cellulitis such that: i. the total affected area involves at least 35 cm2 of erythema, or total affected area of erythema is at least BSA (m2) x 43.0 (cm2/m2), OR ii. alternatively, involves the central face and is associated with an affected area of at least 15 cm2 c. Cellulitis, defined as a diffuse skin infection characterized by spreading areas of erythema, edema and/or induration and: i. is associated with erythema that involves at least 35 cm2 of surface area, or surface area of erythema is at least BSA (m2) x 43.0 (cm2/m2), OR ii. alternatively, cellulitis of the central face that is associated with an affected area of at least 15 cm2 5. In addition to the requirement for erythema, all patients are required to have at least two (2) of the following signs of ABSSSI: a. Purulent drainage/discharge b. Fluctuance c. Heat/localized warmth d. Tenderness to palpation e. Swelling/induration In patients age birth to < 3 months, each patient must meet the following inclusion criteria to be enrolled in this study. Male or female patients from birth to < 3 months of age, including pre-term neonates (gestational age ≥ 32 weeks) A clinical picture compatible with an ABSSSI suspected or confirmed to be caused by Gram-positive bacteria, including MRSA. OR Suspected or confirmed sepsis including any of the following clinical criteria: Hypothermia (<36°C) OR fever (>38.5°C) Bradycardia OR tachycardia OR rhythm instability Hypotension OR mottled skin OR impaired peripheral perfusion Petechial rash New onset or worsening of apnea episodes OR tachypnea episodes OR increased oxygen requirements OR requirement for ventilation support Feeding intolerance OR poor sucking OR abdominal distension Irritability Lethargy Hypotonia In addition, patients must meet at least one of the following laboratory criteria: a. White blood cell count ≤4.0 × 10^9/L OR ≥20.0 × 10^9/L b, Immature to total neutrophil ratio >0.2 c. Platelet count ≤100 × 10^9/L d. C-reactive protein (CRP) >15 mg/L OR procalcitonin ≥ 2 ng/mL e. Hyperglycemia OR Hypoglycemia f. Metabolic acidosis Infections must be of sufficient severity to merit hospitalization and parenteral antibiotic therapy. These infections may include: Cutaneous or subcutaneous abscess Surgical site or traumatic wound infection Cellulitis, Erysipelas Omphalitis Impetigo and bullous impetigo Pustular folliculitis Scarlet fever Staphylococcal scalded skin syndrome Streptococcal toxic shock syndrome Erythematous based-erosion Other infections originating in the skin or subcutaneous tissue and associated with signs and symptoms of sepsis as defined in Inclusion Criterion 2. Patients must be expected to survive with appropriate antibiotic therapy and appropriate supportive care throughout the study. Exclusion Criteria: Patients age 3 months to 17 years: Clinically significant renal impairment, defined as calculated creatinine clearance of less than 30 mL/min. (calculated by the Schwartz bedside formula). Patients birth to < 3 months of age: Moderate or severe renal impairment defined as serum creatinine ≥ 2 times the upper limit of normal (× ULN) for age OR urine output < 0.5 mL/kg/h (measured over at least 8 hours prior to dosing) OR requirement for dialysis. Clinically significant hepatic impairment, defined as serum bilirubin or alkaline phosphatase greater than 2 times the upper limits of normal (ULN) for age, and/or serum aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than 3 times the upper limits of normal (ULN) for age. Treatment with an investigational drug within 30 days preceding the first dose of study medication. Patients with sustained shock defined as systolic blood pressure < 90 mm Hg in children ≥ 10 years old, < 70 mm Hg + [2 x age in years] in children 1 to <10 years, or < 70 mmHg in infants 3 to <12 months old for more than 2 hours despite adequate fluid resuscitation, with evidence of hypoperfusion or need for sympathomimetic agents to maintain blood pressure. More than 24 hours of any systemic antibacterial therapy within 96 hours before randomization. EXCEPTION: Microbiological or clinical treatment failure with a systemic antibiotic other than IV study drug that was administered for at least 48 hours. Failure must be confirmed by either a microbiological laboratory report or documented worsening clinical signs or symptoms. Infection due to an organism known prior to study entry to be resistant to dalbavancin (dalbavancin minimum inhibitory concentration (MIC) greater than 0.25 ug/mL) or vancomycin (vancomycin minimum inhibitory concentration (MIC) greater than 2 ug/mL). Patients with necrotizing fasciitis, or deep-seated infections that would require > 2 weeks of antibiotics (e.g., endocarditis, osteomyelitis or septic arthritis). Infections caused exclusively by Gram-negative bacteria (without Gram-positive bacteria present) and infections caused by fungi, whether alone or in combination with a bacterial pathogen. Venous catheter entry site infection. Infections involving diabetic foot ulceration, perirectal abscess or a decubitus ulcer. Patient with an infected device, even if the device is removed. Examples include infection of: prosthetic cardiac valve, vascular graft, a pacemaker battery pack, joint prosthesis, implantable pacemaker or defibrillator, intraaortic balloon pump, left ventricular assist device, or a neurosurgical device such as a ventricular peritoneal shunt, intra-cranial pressure monitor, or epidural catheter. 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. Patients whose skin infection is the result of having sustained full or partial thickness burns. Patients age 3 months to 17 years, with uncomplicated skin infections such as superficial/simple cellulitis/erysipelas, impetiginous lesion, furuncle, or simple abscess that only requires surgical drainage for cure. Patients birth to < 3 months of age may be enrolled if they have uncomplicated skin infections of sufficient severity to require hospitalization and parenteral antibiotic therapy. Patients age 3 months to 17 years: 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 Anticipated need of antibiotic therapy for longer than 14 days. Patients who are placed in a hyperbaric chamber as adjunctive therapy for the ABSSSI. More than 2 surgical interventions (defined as procedures conducted under sterile technique and typically unable to be performed at the bedside) for the skin infection, or patients who are expected to require more than 2 such interventions. Medical conditions in which chronic inflammation may preclude assessment of clinical response to therapy even after successful treatment (e.g., chronic stasis dermatitis of the lower extremity). 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) for > 14 days prior to enrollment, and known or suspected human immunodeficiency virus (HIV) infected patients with a CD4 cell count< 200 cells/mm3 or with a past or current acquired immunodeficiency syndrome (AIDS)-defining condition and unknown CD4 count. Known or suspected hypersensitivity to glycopeptide antibiotics, betalactam agents, aztreonam, or cephalosporins. 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 patients to have pregnancy testing are those who are at least 10 years old with menarche and/or thelarche (beginning of breast development).

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dalbavancin, single dose<br> | Drug: Dalbavancin single dose<br>* Dalbavancin, weight-adjusted dose, up to 1500mg. Intravenous (IV) administration. Aztreonam may be administered at randomization for presumed co-infection with a Gram-negative pathogen and could be discontinued if a Gram-negative pathogen is not documented by culture. For suspected anaerobic pathogens, metronidazole oral/IV may be used. Patients age birth to <3 months will only receive the single-dose regimen of dalbavancin; any concomitant antibacterial therapy may be administered in this age group based on local standard of care.<br>|
| Experimental: Dalbavancin, two doses<br> | Drug: Dalbavancin two dose<br>* Dalbavancin, weight-adjusted dose, up to 1000mg. Intravenous (IV) administration, with second dalbavancin weight-adjusted dose, up to 500mg. Aztreonam may be administered at randomization for presumed co-infection with a Gram-negative pathogen and could be discontinued if a Gram-negative pathogen is not documented by culture. For suspected anaerobic pathogens, metronidazole oral/IV may be used.<br>|
| Active Comparator: Comparator<br> | Drug: Comparator<br>* Course of either vancomycin not to exceed a total daily dose of 4000 mg;or oxacillin; or flucloxacillin not to exceed a total daily dose of 2000 mg. Intravenous (IV) administration. Possible oral switch after at least 72 hours from oxacillin or flucloxacillin to oral cefadroxil, or from IV vancomycin to oral clindamycin (for MRSA). Aztreonam may be administered at randomization for presumed co-infection with a Gram-negative pathogen and could be discontinued if a Gram-negative pathogen is not documented by culture. For suspected anaerobic pathogens, metronidazole oral/IV may be used. Additional comparator drugs may be used, if an alternate comparator regimen is indicated by local susceptibility patterns. No patient age birth to < 3 months will be randomized to the comparator arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with abnormal audiologic assessment | Audiologic testing will be conducted in at least 20 children < 12 years old, of which at least 9 children will be < 2 years old. Audiologic testing to be conducted on infants (< 12 months old) will include: evoked otoacoustic emissions testing, acoustic immittance measures (tympanometry and contra and ipsilateral acoustic reflex thresholds) and (optional) threshold auditory brainstem responses. For the older children, testing will include evoked otoacoustic emissions testing, acoustic immittance measures (tympanometry and contra ipsilateral acoustic reflex thresholds), and age appropriate behavioral audiologic threshold assessment. Patients with an abnormal audiologic assessment at Day 28 (plus or minus 2 days) that exceeds, by a clinically significant margin, any abnormality observed in the Baseline assessment, will be considered to have an abnormal audiologic assessment | Baseline to Day 28 (± 2 days)] | 
| Change in number of patients with the presence of either Clostridium difficile (CD), vancomycin-resistant enterococci (VRE), or both CD and VRE in bowel flora | Evaluated in patients from birth to < 2 years of age, by performing polymerase chain reaction (PCR) for Clostridium difficile (C diff) and culture for vancomycin-resistant enterococci (VRE) on a stool specimen or rectal swab. | Baseline to Day 28 (± 2 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | Defined as greater than 20% reduction in lesion size compared to baseline. In patients diagnosed with ABSSSI age birth to < 3 months, clinical response at 48-72 hours post-randomization is defined as cessation of increase in lesion size and decreased erythema or tenderness compared to baseline with no appearance of new lesions. In patients diagnosed with sepsis age birth to < 3 months, clinical response at 48-72 hours post-randomization is defined as improvement of at least one abnormal clinical and laboratory parameter related to sepsis. | Baseline to 48 - 72 hours | 
| Clinical response evaluated at the end of treatment (EOT) visit: Cure | Clinical response of Cure will be defined as resolution of the clinical signs and symptoms of infection, when compared to baseline. No additional antibacterial treatment is required for disease under study. | Baseline and Day 14 (± 2 Days) | 
| Clinical response evaluated at the end of treatment (EOT) visit: Improvement | Clinical response of Improvement will be defined as a reduction in severity of two or more, but not all, clinical signs and symptoms of infection, when compared with baseline (patients age 3 months to 17 years and ABSSSI patients age birth to <3 months). In sepsis patients age birth to < 3 months, improvement is defined as reduction in severity of at least one abnormal clinical and laboratory parameter related to sepsis, when compared with baseline. In patients age 3 months to 17 years, no additional antibacterial treatment is required for disease under study. In patients age birth to < 3 months, no rescue antibiotics required after at least 48 hours of start of study treatment. This outcome category will only be used at the EOT evaluation. | Baseline and Day 14 (± 2 Days) | 
| Clinical response evaluated at the end of treatment (EOT) visit: Failure | Clinical response of Failure will be defined as persistence or progression of baseline clinical signs and symptoms of infection after at least 2 days (48 hours) of treatment OR development of new clinical findings consistent with active infection. | Baseline and Day 14 (± 2 Days) | 
| Clinical response evaluated at the end of treatment (EOT) visit: Unknown | Clinical response of Unknown will be defined as extenuating circumstances precluding classification to Cure, Improvement or Failure | Baseline and Day 14 (± 2 Days) | 
| Clinical response evaluated at the test of cure (TOC) visit: Cure | Clinical response of Cure will be defined as resolution of the clinical signs and symptoms of infection, when compared to baseline. No additional antibacterial treatment is required for disease under study. | Baseline and Day 28 (± 2 Days) | 
| Clinical response evaluated at the test of cure (TOC) visit: Failure | Clinical response of Failure will be defined as persistence or progression of baseline clinical signs and symptoms of infection after at least 2 days (48 hours) of treatment OR development of new clinical findings consistent with active infection. | Baseline and Day 28 (± 2 Days) | 
| Clinical response evaluated at the test of cure (TOC) visit: Unknown | Clinical response of Unknown will be defined as extenuating circumstances precluding classification to Cure or Failure | Baseline and Day 28 (± 2 Days) | 
| Clinical response evaluated at follow-up visit: Cure | Clinical response of Cure will be defined as resolution of the clinical signs and symptoms of infection, when compared to baseline. No additional antibacterial treatment is required for disease under study. | Baseline and Day 54 (± 7 days) | 
| Clinical response evaluated at follow-up visit: Failure | Clinical response of Failure will be defined as persistence or progression of baseline clinical signs and symptoms of infection after at least 2 days (48 hours) of treatment OR development of new clinical findings consistent with active infection. | Baseline and Day 54 (± 7 days) | 
| Clinical response evaluated at follow-up visit: Unknown | Clinical response of Unknown will be defined as extenuating circumstances precluding classification to Cure or Failure | Baseline and Day 54 (± 7 days) | 
| Presence of baseline pathogen after treatment | Direct demonstration of eradication or persistence of the causative organism | Baseline to Day 54 (± 7 days) | 
| All-cause mortality: For patients age birth to < 3 months, all-cause mortality will be determined at test of cure (TOC) visit |  | Baseline and Day 28 (± 2 days) | 
| Dalbavancin plasma concentration |  | Within 14 (± 2) days of study drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Bacterial Skin and Skin Structure Infection (ABSSSI)