Phase III Efficacy and Safety Study of AB103 in the Treatment of Patients With Necrotizing Soft Tissue Infections

The primary hypothesis of this study is that in addition to standard of care treatment (which includes surgical intervention, antimicrobial therapy and critical care support for organ dysfunction or failure), AB103 will demonstrate a clinically significant treatment benefit over placebo.

This hypothesis will be addressed by measuring the effect of AB103 on a composite of clinical parameters associated with the disease course of patients with NSTI, using a responder analysis. A responding patient must meet all 5 parameters of the composite clinical success end point, while a non-responding patient can fail by not meeting any one of the parameters. These analyses are designed to demonstrate that in addition to being safe, one dose of 0.5 mg/kg of AB103 will:

Improve systemic signs of the infection by improving organ function of patients compared to placebo as measured by:

• Survival at Day 28
• Modified SOFA (mSOFA) score on Day 14 and change from baseline to Day 14 ≥ 3. A Day 14 mSOFA score of ≤1 and a change from baseline (pre-treatment) to Day 14 ≥3 will be required for a patient to achieve the primary composite clinical success endpoint (NICCE)

Improve the local signs of the infection, as measured by:

• Reduced number of debridements, counted to Day 14. No more than 3 debridements to Day 14 will be required for a patient to achieve composite clinical success
• No amputation after the first debridement (amputation on the first debridement is not considered a failure). A patient will be required to have had no amputations done after the first surgical procedure in order to achieve composite clinical success.

290 patients will be recruited into the study and randomized to receive either 0.5 mg/kg AB103 or placebo in a 1:1 ratio. Randomization will be stratified within center by the diagnosis of Fournier's Gangrene and mSOFA score category (3-4 vs >4) at screening. The study will be conducted with interim analyses for futility at 100 patients and safety monitored by an independent Data Monitoring Board at regular planned intervals.

Inclusion criteria

• Surgical confirmation of NSTI by attending surgeon;
• mSOFA score ≥3 (in any one or combination of the 5 major components of SOFA score with one organ component having a score of at least 2: cardiovascular, respiratory, renal, coagulation, CNS), measured as close as possible to the first debridement;
• IV drug administration within 6 hours from the clinical diagnosis and the decision at the study site, to have an urgent surgical exploration and debridement (drug should not be administered until surgical confirmation is established);
• If a woman is of childbearing potential, she must consistently use an acceptable method of contraception from baseline through Day 28;
• If a male patient's sexual partner is of childbearing potential, the male patient must acknowledge that they will consistently use an acceptable method of contraception (defined above) from baseline through Day 28.
• Signed and dated informed consent (ICF) as defined by the Institutional Review Board (IRB) and, if applicable, California Bill of Rights. If patient is unable to comprehend or sign the ICF, patient's legally acceptable representative may sign the ICF

Exclusion criteria

• BMI>51;
• Patient who has been operated at least once for the current NSTI infection and had a curative deep tissue debridement;
• Patients with overt peripheral vascular disease in the involved area ;
• Diabetic patients with peripheral vascular disease who present with below the ankle infection;
• Removed deep vein thrombosis (DVT) in area of NSTI as an exclusion criteria
• Patient with burn wounds;
• Current condition of: (a) Inability to maintain a mean arterial pressure > 50 mmHg and/or systolic blood pressure > 70 mmHg for at least 1 hour prior to screening despite the presence of vasopressors and IV fluids or (b) a patient with respiratory failure such that an SaO2 of 80% cannot be achieved or (c) a patient with refractory coagulopathy (INR >5) or thrombocytopenia (platelet count <20,000) that does not partially correct with administration of appropriate factors or blood products;
• Chronic neurological impairment that leads to a neuro mSOFA component ≥2;
• Recent cerebrovascular accident in the last 3 months;
• Patients with cardiac arrest requiring cardiopulmonary resuscitation within the past 30 days;
• Patient is not expected to survive throughout 28 days of study due to underlying medical condition, such as poorly controlled neoplasm;
• Patient or patient's family are not committed to aggressive management of the patient's condition;
• Any concurrent medical condition, which in the opinion of the Investigator, may compromise the safety of the patient or the objectives of the study or the patient will not benefit from treatment such as:

• Congestive heart failure (CHF){ New York Heart Association (NYHA) class III-IV}
• Severe chronic pulmonary obstructive disease (COPD)
• Liver dysfunction {Childs-Pugh class C}
• Immunosuppression (see Appendix F, Section 15.6 for list of excluded immunosuppressive medications)
• Neutropenia < 1,000 cells/mm3not due to the underlying infection
• Idiopathic Thrombocytopenia Purpura
• Receiving or about to receive chemotherapy or biologic anti-cancer treatment although hormonal manipulation therapies for breast and prostate malignancies are permitted
• Hematological and lymphatic malignancies in the last 5 years;
• Known HIV infection with CD4 (cluster of differentiation 4) count < 200 cells/mm3 or < 14% of all lymphocytes;
• Patients with known chronic kidney disease (documented pre-illness creatinine value(s) ≥2.0) or patients receiving renal replacement therapy for chronic kidney disease;
• Patients that are treated with continuous hemofiltration (e.g. Continuous Veno-Venous Hemofiltration) for acute kidney dysfunction, not due to NSTI, starting prior to study drug administration;
• Pregnant or lactating women;
• Previous enrollment in a clinical trial involving investigational drug or a medical device within 30 days;
• Previous enrollment in this protocol, ATB-202 or the Phase 2 trial of AB103, ATB-201.