| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute bacterial skin and skin structure infection. For Cohort 5 (from birth to less than 3 months) also patients with sepsis are allowed. |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Microbiological Phenomena [G06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066412 |
| E.1.2 | Term | Staphylococcus aureus skin infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037633 |
| E.1.2 | Term | Pyoderma (skin infection) |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040873 |
| E.1.2 | Term | Skin infection aggravated |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040872 |
| E.1.2 | Term | Skin infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040875 |
| E.1.2 | Term | Skin infection pyogenic |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040874 |
| E.1.2 | Term | Skin infection NOS |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066409 |
| E.1.2 | Term | Staphylococcal skin infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040047 |
| E.1.2 | Term | Sepsis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 determine the safety and descriptive efficacy of dalbavancin for the treatment of acute bacterial skin and skin structure infections in children from birth to 17 years(inclusive), known or suspected to be caused by susceptible Gram-positive organisms, including methicillin-resistant strains of Staphylococcus aureus |
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| E.2.2 | Secondary objectives of the trial |
To assess clinical response by baseline pathogen at 48-72 h post randomization ( ≥ 20% reduction in lesion size compared to baseline), and clinical response by baseline pathogen based on the global clinical assessment by the investigator at EoT(14 ± 2 days after start of therapy), at TOC visit (28 ± 2 days after start of therapy), and at last follow-up visit (54 ± 7 days after start of therapy).
Cohort 5 ABSSSI patients: clinical response by baseline pathogen defined as cessation of increase in lesion size and decreased erythema or tenderness compared to baseline with no new lesions.
Cohort 5 diagnosed with sepsis: clinical response at 48-72 hours post-randomization defined as improvement of at least one abnormal clinical and laboratory parameters related to sepsis.
Cohort 5 : to assess all-cause mortality at test of cure visit (28 ± 2 days after start of therapy).
To evaluate the pharmacokinetics of dalbavancin in pediatric patients from birth to 17 years of age.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Cohort 1 to 4:
- Male or female patients 3 months -17 years of age
- A clinical picture compatible with an ABSSSI suspected or confirmed to be caused by Gram-positive bacteria, including 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)
• 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:
(a) 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
- Patients must be expected to survive with appropriate antibiotic therapy and appropriate supportive care throughout the study.
For Cohort 5 (birth to < 3 months), each patient must meet the following inclusion criteria to be enrolled in this study.
1. Male or female patients from birth to < 3 months of age, including pre-term neonates (gestational age ≥ 32 weeks)
2. 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:
(a) Hypothermia (<36°C) OR fever (>38.5°C)
(b) Bradycardia OR tachycardia OR rhythm instability
(c) Hypotension OR mottled skin OR impaired peripheral perfusion
(d) Petechial rash
(e) New onset or worsening of apnea episodes OR tachypnea episodes OR increased oxygen requirements OR requirement for ventilation support
(f) Feeding intolerance OR poor sucking OR abdominal distension
(g) Irritability
(h) Lethargy
(i) Hypotonia
3. In addition, patients must meet at least one of the following laboratory criteria:
(a) White blood cell count ≤4.0 × 109/L OR ≥20.0 × 109/L
(b) Immature to total neutrophil ratio >0.2
(c) Platelet count ≤100 × 109/L
(d) C-reactive protein (CRP) >15 mg/L OR procalcitonin ≥ 2 ng/mL
(e) Hyperglycemia OR Hypoglycemia
(f) Metabolic acidosis
4. Infections must be of sufficient severity to merit hospitalization and parenteral antibiotic therapy. These infections may include:
(a) Cutaneous or subcutaneous abscess
(b) Surgical site or traumatic wound infection
(c) Cellulitis, Erysipelas
(d) Omphalitis
(e) Impetigo and bullous impetigo
(f) Pustular folliculitis
(g) Scarlet fever
(h) Staphylococcal scalded skin syndrome
(i) Streptococcal toxic shock syndrome
(j) Erythematous based-erosion
(k) Other infections originating in the skin or subcutaneous tissue and associated with signs and symptoms of sepsis as defined in Inclusion Criterion 2.
5. A signed and dated informed consent document indicating that a legally acceptable representative or the patient’s parent(s)/legal guardian(s) has been informed of all pertinent aspects of the trial.
6. Each patients’ parent(s)/legal guardian(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 test and other outpatient procedures as required by the protocol.
7. Patients 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 |
- Clinically significant renal impairment, defined as calculated creatinine clearance < 30 mL/min. Patients in Cohort 5 (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 >2X ULN for age, and/or serum AST or ALT >3X ULN for age.
- 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.
- 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, intra-aortic 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.
- Cohort 1 to 4: Patients with uncomplicated skin infections such as superficial/simple cellulitis/erysipelas, impetiginous lesion, furuncle, or simple abscess that only requires surgical drainage for cure. Patients in Cohort 5 (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.
- For Cohorts 1 – 4 :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.
- Patients with a rapidly fatal illness, who are not expected to survive for 3 months.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint includes all safety parameters:
- Safety will be assessed by means of physical examination and vital signs, collection of adverse events and clinical laboratory tests.
- Audiologic testing will be conducted in at least 20 children < 12 years old (in selected centers), of which at least 9 children will be <2 years old. The impact of dalbavancin on the bowel flora will be determined in all patients from birth to < 2 years, by performing PCR for Clostridium difficile (C. diff) and culture for vancomycin resistant enterococci (VRE) on a stool specimen or rectal swab. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Physical examination: Baseline
- Vital signs: Baseline, and at Day 1, 48-72 hours post randomization, Day 8 (± 1 day), Day 14 (± 2 days), Day 28 (± 2 days), Day 54 (± 7 days), or at premature discontinuation
- Adverse events: every visit,
- Clinical laboratory tests: Baseline and at Day 14 (± 2 days), or at premature discontinuation.
- Audiologic testing : Baseline and repeated at Day 28 (± 2 days). If the audiologic
assessment at Day 28 shows an abnormality : follow-up assessments will be
performed at 3 months and 6 months post-dose, as needed or until returned to baseline.
- The impact of dalbavancin on the bowel flora: Baseline and Day 28 (± 2days). The testing of bowel flora in this age group will be done in all study arms. |
|
| E.5.2 | Secondary end point(s) |
Cohort 1 to 4: Clinical response at 48-72 hours after randomization defined as ≥ 20% reduction in lesion size compared to baseline, in patients who did not receive rescue therapy and are alive.
Cohort 5 (birth to < 3 months): clinical response in patients with ABSSSI 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 in Cohort 5, clinical response at 48-72 hours post-randomization is defined as improvement of at least one abnormal clinical and laboratory parameter related to sepsis. Clinical response, in each of the 5 cohorts, will be assessed in patients who did not receive rescue therapy and are alive (in Cohort 5, rescue therapy is defined as additional antibiotic therapy initiated after at least 48 hours of start of study treatment) .
Microbiological outcome
Pharmacokinetic outcome
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinical response and microbiology outcome:
Baseline, 48-72 hours post randomization, EOT visit (14 ± 2 days), TOC visit (28 ± 2 days) and follow up visit (54 ± 7 days). All-cause mortality: For Cohort 5 only (birth to < 3 months), all-cause mortality will be determined at test of cure visit (28 ± 2 days after start of therapy).
Plasma PK samples will be collected on all patients on dalbavancin (single dose arm and two-dose arm), at 30 minutes and at 2 hours (Day 1), at 48-72 hours (Day 3-4), at 168 ± 24 hours (Day 8 ± 1) before the Day 8 dalbavancin dose, and at 312 ± 48 hours (Day 14 ± 2) and at premature discontinuation. |
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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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| 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 |
| Belarus |
| Brazil |
| Bulgaria |
| Chile |
| Colombia |
| Ecuador |
| Georgia |
| Greece |
| Guatemala |
| Latvia |
| Lithuania |
| Mexico |
| Panama |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| 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
|
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 | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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