Study to Evaluate the Safety and Tolerability of Single-Dose Intravenous (IV) Oritavancin

Study Overview
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Brief Summary
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This protocol describes a randomized, open-label study to evaluate the safety and tolerability of single-dose intravenous (IV) oritavancin diphosphate (oritavancin) versus standard of care (SoC) antibiotics for the treatment of pediatric subjects with acute bacterial skin and skin structure infections (ABSSSIs). This study involves two oritavancin products, ORBACTIV® and KIMYRSATM. Oritavancin is the active drug substance in both ORBACTIV and KIMYRSA. This study protocol distinguishes the differences between ORBACTIV and KIMYRSA by providing product-specific data, and information and guidance for Investigators. Oritavancin is used to describe drug product data, and information and guidance that is not specific to ORBACTIV or KIMYRSA (i.e., applies to both). The study involves pharmacokinetic (PK) sampling and will evaluate clinical outcome assessments. The study was designed to capture adequate data while minimizing the impact to subjects and their caregivers.

Official Title
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A Multicenter, Open-Label, Evaluator-Blinded, Randomized Study to Evaluate the Safety and Tolerability of Single-Dose IV Oritavancin vs SoC for the Treatment of Pediatric Subjects With Acute Bacterial Skin and Skin Structure Infections

Conditions
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Acute Bacterial Skin and Skin Structure Infection

Intervention / Treatment
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* Drug: Oritavancin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 3 months to <18 years of age at randomization Diagnosis of at least one of the following ABSSSI infections (known or suspected to be caused by a gram-positive pathogen): Wound infection: that is either traumatic or surgical in origin, defined as an infection characterized by purulent drainage from a wound with surrounding erythema, edema, and/or induration Cellulitis/erysipelas: a diffuse skin infection characterized by spreading areas of erythema, edema, and/or induration Major cutaneous abscess: an infection characterized by a collection of pus within the dermis or subcutaneous tissue that is accompanied by surrounding erythema, edema, and/or induration ABSSSI must present with at least two of the following signs and symptoms: Purulent drainage or discharge Erythema (>1 cm beyond edge of wound or abscess) Fluctuance Heat or localized warmth Edema/induration Pain or tenderness to palpation AND at least one of the following signs of systemic inflammation: Proximal lymph node swelling and tenderness Increased temperature (>38.0°C [>100.4°F]) Decreased temperature (<36.0°C [<96.8°F]) Decreased white blood count (WBC) (<4000/mm3) or increased WBC (>12,000mm3) Bandemia >10% C-reactive protein (CRP) >upper limit of normal (ULN) Written informed consent obtained from parent(s) or legal guardian(s), with written or documented verbal assent of the child obtained, when appropriate, before initiation of any assessments conducted solely for study purposes. Exclusion Criteria: Subjects who have received more than 72 hours of effective antibacterial drug therapy for treatment of the current episode of ABSSSI Subjects who have received a glycopeptide antibiotic (e.g., vancomycin, telavancin, teicoplanin) within 24 hours of randomization Subjects who have received dalbavancin within 45 days prior to randomization Subjects who have been treated with oritavancin within the last 50 days Subjects with infection suspected to be associated with a device or implant Subjects with septic shock or hemodynamic instability Subjects with ABSSSI due to, or associated with any of the following: Infection suspected or documented to be caused solely by gram-negative pathogens (e.g., human or animal bite, injury contaminated with fresh or saltwater, external malignant otitis), fungi, or viruses Wound infection (surgical or traumatic) or abscess with only gram-negative pathogens Concomitant infection at another site, not including a secondary ABSSSI lesion (e.g., septic arthritis, endocarditis, osteomyelitis). Infected burn Primary infection superimposed on a pre-existing skin disease with associated inflammatory changes, e.g., atopic dermatitis, eczema Any evolving necrotizing process (e.g., necrotizing fasciitis), gangrene, or infection suspected or proven to be caused by clostridioides species (e.g., crepitance on examination of the ABSSSI site and/or surrounding tissue(s), radiographic evidence of subcutaneous gas in proximity to the infection) Clinically significant viral infection (e.g., influenza, COVID-19) which, in the Investigator's judgement, will impact the study clinical outcome assessments (e.g., subject is febrile due to the viral infection) Subjects currently receiving chronic systemic immunosuppressive therapy Subjects with neutropenia, defined as absolute neutrophil count (ANC) <500 cells/mm3 Creatinine clearance (CrCl) < 30 mL/min/1.73 m2 as calculated using the updated Schwartz bedside formula: eGFR = k x (height in cm) ÷ serum Creatinine k = 0.33 in pre-term infants. k = 0.45 in term infants to 1 year of age. k = 0.55 in children and adolescent girls. k = 0.70 in adolescent boys Menstruating females with a positive result for the urine or serum human chorionic gonadotropin (HCG) test administered at screening Females of childbearing potential (and males with female partners of childbearing potential) unwilling to practice abstinence or use at least two methods of contraception (e.g., oral contraceptives, barrier methods, approved contraceptive implants) during the entire study period Subjects with a history of infusion-related immunoglobulin E (IgE)-mediated allergic reaction or hypersensitivity reaction to glycopeptides (e.g., vancomycin, telavancin, dalbavancin, oritavancin, teicoplanin) or any of their excipients Subjects who are taking heparin (other than heparin flush for line patency) or warfarin, and/or require anticoagulant monitoring [activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR)] Subjects receiving treatment with an investigational medicinal product or investigational device within 3 months before enrollment or during the study Subjects whom the investigator considers unlikely to adhere to the protocol, comply with Study Drug administration, or complete the clinical study (e.g., unlikely to survive 28 days from initiation of Study Drug) Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x ULN or total bilirubin ≥2x ULN.

Ages Eligible for Study
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Minimum Age: 3 Months
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: Orbactiv<br>ORBACTIV is infused at 15mg/kg over 3 hours for all subjects not to exceed a dose of 1200mg. | Drug: Oritavancin<br>* Oritavancin for IV infusion<br>|
| Experimental: Kimyrsa<br>KIMYRSA is infused at 15mg/kg over 1 hour for subjects ≥12 years old and weighing >40 kg not to exceed a dose of 1200mg. KIMYRSA is infused at 15mg/kg over 3 hours in subjects <12 years old or weighing ≤40 kg. | Drug: Oritavancin<br>* Oritavancin for IV infusion<br>|
| Active Comparator: Standard of Care<br>The following SoC medications below will be administered via IV infusion, per the package insert, and according to local rules and regulations. SoC medications cannot be used in combination with one another. Vancomycin Teicoplanin Clindamycin Daptomycin Semi-synthetic penicillins (e.g., nafcillin, oxacillin, cloxacillin) Cefazolin Ceftaroline | Drug: Oritavancin<br>* Oritavancin for IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Assessments | Adverse events (AEs) | 28 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Test of Cure | All-cause mortality assessed at the Test of Cure visit. | Day 28 | 
| Clinical Outcome Assessments | Clinical Outcome Definitions: Clinical response of Cure or failure at End of Treatment visit and Test of Cure visit. Cure Complete or nearly complete resolution of baseline signs and symptoms of the primary infection, including absence of fever No further treatment with antibiotics required for the primary infection Failure Use of additional antibiotic treatment for the primary infection prior to the visit (other than for gram-negative coverage, when given according to this protocol) Worsening signs and symptoms (either assessed by the investigational site or reported by the subject or subject's caregivers) of the primary infection >72 hours from the start of Study Drug treatment. Lost to Follow-up or other extenuating circumstance where the subject cannot be adequately assessed | EoT Day 14; ToC Day 28 |