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

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.


Eligibility Criteria:
Inclusion Criteria:

1. Male or female, 3 months to \<18 years of age at randomization
2. Diagnosis of at least one of the following ABSSSI infections (known or suspected to be caused by a gram-positive pathogen):

   1. 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
   2. Cellulitis/erysipelas: a diffuse skin infection characterized by spreading areas of erythema, edema, and/or induration
   3. 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
3. ABSSSI must present with at least two of the following signs and symptoms:

   1. Purulent drainage or discharge
   2. Erythema (\>1 cm beyond edge of wound or abscess)
   3. Fluctuance
   4. Heat or localized warmth
   5. Edema/induration
   6. Pain or tenderness to palpation AND at least one of the following signs of systemic inflammation:

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   1. Proximal lymph node swelling and tenderness
   2. Increased temperature (\>38.0°C \[\>100.4°F\])
   3. Decreased temperature (\<36.0°C \[\<96.8°F\])
   4. Decreased white blood count (WBC) (\<4000/mm3) or increased WBC (\>12,000mm3)
   5. Bandemia \>10%
   6. C-reactive protein (CRP) \>upper limit of normal (ULN)
4. 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:

1. Subjects who have received more than 72 hours of effective antibacterial drug therapy for treatment of the current episode of ABSSSI
2. Subjects who have received a glycopeptide antibiotic (e.g., vancomycin, telavancin, teicoplanin) within 24 hours of randomization
3. Subjects who have received dalbavancin within 45 days prior to randomization
4. Subjects who have been treated with oritavancin within the last 50 days
5. Subjects with infection suspected to be associated with a device or implant
6. Subjects with septic shock or hemodynamic instability
7. Subjects with ABSSSI due to, or associated with any of the following:

   1. 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
   2. Wound infection (surgical or traumatic) or abscess with only gram-negative pathogens
   3. Concomitant infection at another site, not including a secondary ABSSSI lesion (e.g., septic arthritis, endocarditis, osteomyelitis).
   4. Infected burn
   5. Primary infection superimposed on a pre-existing skin disease with associated inflammatory changes, e.g., atopic dermatitis, eczema
   6. 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)
   7. 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)
8. Subjects currently receiving chronic systemic immunosuppressive therapy
9. Subjects with neutropenia, defined as absolute neutrophil count (ANC) \<500 cells/mm3
10. 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
11. Menstruating females with a positive result for the urine or serum human chorionic gonadotropin (HCG) test administered at screening
12. 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
13. 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
14. Subjects who are taking heparin (other than heparin flush for line patency) or warfarin, and/or require anticoagulant monitoring \[activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR)\]
15. Subjects receiving treatment with an investigational medicinal product or investigational device within 3 months before enrollment or during the study
16. 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)
17. Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3x ULN or total bilirubin ≥2x ULN.