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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 199
- 试验地点
- 84
- 主要终点
- Shift From Baseline in Distortion Product Otoacoustic Emission at TOC Visit
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
- •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
- •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
- •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
- •Patients must be expected to survive with appropriate antibiotic therapy and appropriate supportive care throughout the study.
排除标准
- •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).
研究组 & 干预措施
Dalbavancin single-dose
Participants received dalbavancin administered intravenously as follows: birth to < 3 months old and 3 months to < 6 years old: 22.5 mg/kg (maximum 1500 mg) on Day 1; ≥6 years to 17 years old (inclusive): 18 mg/kg (maximum 1500 mg) on Day 1. Participants aged birth to < 3 months were not randomized; all received dalbavancin single-dose.
干预措施: Dalbavancin (Drug)
Dalbavancin two-dose
Participants received dalbavancin administered intravenously as follows: 3 months to < 6 years old: 15 mg/kg (maximum 1000 mg) on Day 1, and 7.5 mg/kg (maximum 500 mg) on Day 8; ≥6 years to 17 years old (inclusive): 12 mg/kg (maximum 1000 mg) on Day 1, and 6 mg/kg (maximum 500 mg) on Day 8.
干预措施: Dalbavancin (Drug)
Comparator
Participants 3 mos to < 6 yrs old and ≥6 yrs to 17 yrs old received a 10-14 day course of either vancomycin 10 to 15 mg/kg/dose, not to exceed a 4000 mg total daily dose; or oxacillin 30 mg/kg/dose, infused over 60 (± 10) mins every 6 (± 1) hrs; or flucloxacillin 50 mg/kg/dose, infused over 60 (± 10) mins every 6 (± 1) hrs, not to exceed a 2000 mg total daily dose. Vancomycin was to be taken for methicillin-resistant Gram-positive infections. Based on local practice patterns/approvals for clinical use in the pediatric population, oxacillin or flucloxacillin were supplied as an IV comparator. At investigator's discretion, after 72 hrs of IV therapy, those on oxacillin or flucloxacillin could switch to oral cefadroxil (dose for infants/children: 15 mg/kg/dose every 12 hrs, max 2 g/day; dose for adolescents: 500-1000 mg every 12 hrs), and if infection with methicillin-resistant S. aureus was confirmed, those on vancomycin were allowed to switch to oral clindamycin 10 mg/kg every 8 hrs.
干预措施: Vancomycin (Drug)
Comparator
Participants 3 mos to < 6 yrs old and ≥6 yrs to 17 yrs old received a 10-14 day course of either vancomycin 10 to 15 mg/kg/dose, not to exceed a 4000 mg total daily dose; or oxacillin 30 mg/kg/dose, infused over 60 (± 10) mins every 6 (± 1) hrs; or flucloxacillin 50 mg/kg/dose, infused over 60 (± 10) mins every 6 (± 1) hrs, not to exceed a 2000 mg total daily dose. Vancomycin was to be taken for methicillin-resistant Gram-positive infections. Based on local practice patterns/approvals for clinical use in the pediatric population, oxacillin or flucloxacillin were supplied as an IV comparator. At investigator's discretion, after 72 hrs of IV therapy, those on oxacillin or flucloxacillin could switch to oral cefadroxil (dose for infants/children: 15 mg/kg/dose every 12 hrs, max 2 g/day; dose for adolescents: 500-1000 mg every 12 hrs), and if infection with methicillin-resistant S. aureus was confirmed, those on vancomycin were allowed to switch to oral clindamycin 10 mg/kg every 8 hrs.
干预措施: Oxacillin (Drug)
Comparator
Participants 3 mos to < 6 yrs old and ≥6 yrs to 17 yrs old received a 10-14 day course of either vancomycin 10 to 15 mg/kg/dose, not to exceed a 4000 mg total daily dose; or oxacillin 30 mg/kg/dose, infused over 60 (± 10) mins every 6 (± 1) hrs; or flucloxacillin 50 mg/kg/dose, infused over 60 (± 10) mins every 6 (± 1) hrs, not to exceed a 2000 mg total daily dose. Vancomycin was to be taken for methicillin-resistant Gram-positive infections. Based on local practice patterns/approvals for clinical use in the pediatric population, oxacillin or flucloxacillin were supplied as an IV comparator. At investigator's discretion, after 72 hrs of IV therapy, those on oxacillin or flucloxacillin could switch to oral cefadroxil (dose for infants/children: 15 mg/kg/dose every 12 hrs, max 2 g/day; dose for adolescents: 500-1000 mg every 12 hrs), and if infection with methicillin-resistant S. aureus was confirmed, those on vancomycin were allowed to switch to oral clindamycin 10 mg/kg every 8 hrs.
干预措施: Flucloxacillin (Drug)
Comparator
Participants 3 mos to < 6 yrs old and ≥6 yrs to 17 yrs old received a 10-14 day course of either vancomycin 10 to 15 mg/kg/dose, not to exceed a 4000 mg total daily dose; or oxacillin 30 mg/kg/dose, infused over 60 (± 10) mins every 6 (± 1) hrs; or flucloxacillin 50 mg/kg/dose, infused over 60 (± 10) mins every 6 (± 1) hrs, not to exceed a 2000 mg total daily dose. Vancomycin was to be taken for methicillin-resistant Gram-positive infections. Based on local practice patterns/approvals for clinical use in the pediatric population, oxacillin or flucloxacillin were supplied as an IV comparator. At investigator's discretion, after 72 hrs of IV therapy, those on oxacillin or flucloxacillin could switch to oral cefadroxil (dose for infants/children: 15 mg/kg/dose every 12 hrs, max 2 g/day; dose for adolescents: 500-1000 mg every 12 hrs), and if infection with methicillin-resistant S. aureus was confirmed, those on vancomycin were allowed to switch to oral clindamycin 10 mg/kg every 8 hrs.
干预措施: Cefadroxil (Drug)
Comparator
Participants 3 mos to < 6 yrs old and ≥6 yrs to 17 yrs old received a 10-14 day course of either vancomycin 10 to 15 mg/kg/dose, not to exceed a 4000 mg total daily dose; or oxacillin 30 mg/kg/dose, infused over 60 (± 10) mins every 6 (± 1) hrs; or flucloxacillin 50 mg/kg/dose, infused over 60 (± 10) mins every 6 (± 1) hrs, not to exceed a 2000 mg total daily dose. Vancomycin was to be taken for methicillin-resistant Gram-positive infections. Based on local practice patterns/approvals for clinical use in the pediatric population, oxacillin or flucloxacillin were supplied as an IV comparator. At investigator's discretion, after 72 hrs of IV therapy, those on oxacillin or flucloxacillin could switch to oral cefadroxil (dose for infants/children: 15 mg/kg/dose every 12 hrs, max 2 g/day; dose for adolescents: 500-1000 mg every 12 hrs), and if infection with methicillin-resistant S. aureus was confirmed, those on vancomycin were allowed to switch to oral clindamycin 10 mg/kg every 8 hrs.
干预措施: Clindamycin (Drug)
结局指标
主要结局
Shift From Baseline in Distortion Product Otoacoustic Emission at TOC Visit
时间窗: Baseline, Day 28 (± 2 days)
Audiologic testing was to be conducted in at least 20 children \< 12 years old, of which at least 9 children were \< 2 years old. Audiologic testing conducted on infants (\< 12 months old) included: 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 included evoked otoacoustic emissions testing, acoustic immittance measures (tympanometry and contra ipsilateral acoustic reflex thresholds), and age appropriate behavioral audiologic threshold assessment. Participants with an abnormal audiologic assessment at Day 28 (± 2 days) that exceeded, by a clinically significant margin, any abnormality observed in the Baseline assessment, were considered to have an abnormal audiologic assessment.
Shift From Baseline in Auditory Brainstem Response Test at TOC Visit
时间窗: Baseline, Day 28 (± 2 days)
Audiologic testing was to be conducted in at least 20 children \< 12 years old, of which at least 9 children were \< 2 years old. Audiologic testing conducted on infants (\< 12 months old) included: 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 included evoked otoacoustic emissions testing, acoustic immittance measures (tympanometry and contra ipsilateral acoustic reflex thresholds), and age appropriate behavioral audiologic threshold assessment. Participants with an abnormal audiologic assessment at Day 28 (± 2 days) that exceeded, by a clinically significant margin, any abnormality observed in the Baseline assessment, were considered to have an abnormal audiologic assessment.
Shift From Baseline in Acoustic Immittance Test at TOC Visit
时间窗: Baseline, Day 28 (± 2 days)
Audiologic testing was to be conducted in at least 20 children \< 12 years old, of which at least 9 children were \< 2 years old. Audiologic testing conducted on infants (\< 12 months old) included: 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 included evoked otoacoustic emissions testing, acoustic immittance measures (tympanometry and contra ipsilateral acoustic reflex thresholds), and age appropriate behavioral audiologic threshold assessment. Participants with an abnormal audiologic assessment at Day 28 (± 2 days) that exceeded, by a clinically significant margin, any abnormality observed in the Baseline assessment, were considered to have an abnormal audiologic assessment.
Shift From Baseline in Behavioral Audiometric Valuation at TOC Visit
时间窗: Baseline, Day 28 (± 2 days)
Audiologic testing was to be conducted in at least 20 children \< 12 years old, of which at least 9 children were \< 2 years old. Audiologic testing conducted on infants (\< 12 months old) included: 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 included evoked otoacoustic emissions testing, acoustic immittance measures (tympanometry and contra ipsilateral acoustic reflex thresholds), and age appropriate behavioral audiologic threshold assessment. Participants with an abnormal audiologic assessment at Day 28 (± 2 days) that exceeded, by a clinically significant margin, any abnormality observed in the Baseline assessment, were considered to have an abnormal audiologic assessment.
Shift From Baseline in Clostridium Difficile (CD) and Vancomycin-resistant Enterococci (VRE) at TOC Visit
时间窗: Baseline, Day 28 (± 2 days)
Bowel flora was evaluated in participants from birth to \< 2 years of age by performing polymerase chain reaction (PCR) analysis for Clostridium difficile (C diff) and culture for vancomycin-resistant enterococci (VRE) on a stool specimen or rectal swab. Samples were analyzed at Baseline and at the Test of Cure (TOC) visit.
次要结局
- Clinical Response at 48-72 Hours(Baseline, 48-72 hours)
- Clinical Response at the End of Treatment (EOT) Visit (Investigator Assessment of Clinical Outcome)(Baseline, Day 14 (± 2 Days))
- Clinical Response at the End of Treatment (EOT) Visit (Clinical Response by Sponsor)(Baseline, Day 14 (± 2 Days))
- Clinical Response at the Test of Cure (TOC) Visit (Investigator Assessment of Clinical Outcome)(Baseline, Day 28 (± 2 Days))
- Clinical Response at the Test of Cure (TOC) Visit (Clinical Response by Sponsor)(Baseline, Day 28 (± 2 Days))
- Clinical Response at the Follow-Up Visit (Investigator Assessment of Clinical Outcome)(Baseline, Day 54 (± 7 days))
- Clinical Response at the Follow-Up Visit (Clinical Response by Sponsor)(Baseline, Day 54 (± 7 days))
- Clinical Response by Baseline Pathogen at 48-72 Hours (Clinical Response by Sponsor)(Baseline, 48-72 hours)
- Clinical Response by Baseline Pathogen at the End of Treatment (EOT) Visit (Investigator Assessment of Clinical Outcome)(Baseline, Day 14 (± 2 Days))
- Clinical Response by Baseline Pathogen at the End of Treatment (EOT) Visit (Clinical Response by Sponsor)(Baseline, Day 14 (± 2 Days))
- Clinical Response by Baseline Pathogen at the Test of Cure (TOC) Visit (Investigator Assessment of Clinical Outcome)(Baseline, Day 28 (± 2 Days))
- Clinical Response by Baseline Pathogen at the Test of Cure (TOC) Visit (Clinical Response by Sponsor)(Baseline, Day 28 (± 2 Days))
- Clinical Response by Baseline Pathogen at the Follow-up Visit (Investigator Assessment of Clinical Outcome)(Baseline, Day 54 (± 7 days))
- Clinical Response by Baseline Pathogen at the Follow-up Visit (Clinical Response by Sponsor)(Baseline, Day 54 (± 7 days))
- Microbiological Response at 48-72 Hours(Baseline, 48-72 hours)
- Microbiological Response at the End of Treatment (EOT) Visit(Baseline, Day 14 (± 2 Days))
- Microbiological Response at the Test of Cure (TOC) Visit(Baseline, Day 28 (± 2 Days))
- Microbiological Response at the Follow-Up Visit(Baseline, Day 54 (± 7 days))
- Microbiological Response at 48-72 Hours by Baseline Gram-positive Pathogen(Baseline, 48-72 hours)
- Microbiological Response at the End of Treatment (EOT) Visit by Baseline Gram-positive Pathogen(Baseline, Day 14 (± 2 Days))
- Microbiological Response at the Test of Cure (TOC) Visit by Baseline Gram-positive Pathogen(Baseline, Day 28 (± 2 Days))
- Microbiological Response at the Follow-Up Visit by Baseline Gram-positive Pathogen(Baseline, Day 54 (± 7 days))
- All-cause Mortality at the Test of Cure (TOC) Visit Among Cohort 5 Participants(Day 28 (± 2 Days))
- Concentration of Dalbavancin in Plasma(30 min (end of infusion on Day 1); 2 hrs after start of IV (Day 1); and 48-72 hrs, 168 hrs, and 312 hrs after start of IV)