Evaluation of Safety, PK and Immunomodulatory Effects of AB103 in Necrotizing Soft Tissue Infections Patients

Study Overview
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Brief Summary
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A study to evaluate the safety and pharmacokinetics profile of different doses of AB103 administered to patients diagnosed with Necrotizing Soft Tissue Infections that are scheduled for an urgent surgical intervention as part of their standard of care.

Detailed Description
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A study to evaluate the safety and pharmacokinetics profile of different doses of AB103 administered to patients diagnosed with Necrotizing Soft Tissue Infections that are scheduled for an urgent surgical intervention as part of their standard of care. The primary study hypothesis is that AB-103 can be administered safely to the patients presenting with Necrotizing Soft Tissue Infections. Secondary endpoints are efficacy by exploratory descriptive analyses of specific efficacy endpoints from three outcome domains to demonstrate treatment benefit of AB103 in comparison to placebo in patients with Necrotizing Soft Tissue Infections. The efficacy domains are: Clinical status domain Pharmacoeconomics domain Systemic and local inflammatory biomarker domain

Official Title
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Evaluation of Safety, Pharmacokinetics and Immunomodulatory Effects of AB103, a CD28 Co-stimulatory Receptor Antagonist, in Patients Diagnosed With Necrotizing Soft Tissue Infections

Conditions
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Necrotizing Soft Tissue Infections

Intervention / Treatment
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* Drug: AB103
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Clinical diagnosis of NSTI due to bacterial infection (Necrotizing Fasciitis, Group A streptococcal infection or non group A streptococcal infection, Fournier's gangrene, Bacterial synergistic gangrene, Synergistic Necrotizing Cellulitis, Clostridial gas gangrene/ myonecrosis) that may be supported by specific signs and symptoms, e.g. tense edema outside area of compromised skin, pain disproportionate to appearance, skin discoloration, ecchymosis, blisters/bullae, necrosis, tense edema, crepitus and/or subcutaneous gas AND a decision for urgent surgical exploration and debridement; Patient who did not receive the study drug prior to the surgery need to have a definite diagnosis of NSTI confirmed surgically (e.g. presence of necrotic tissue, thrombosed vessels in the subcutaneous tissue, lack of bleeding and dishwater (cloudy, thin, gray) fluid) in order to get the drug during or after operation; IV drug administration within 6 hours from the clinical diagnosis and from the documented decision to have an urgent surgical exploration and debridement; Signed and dated ICF as defined by the IRB and, if applicable, California Bill of Rights. By signing the ICF, the patient agrees to release any medical records pursuant to current Health Insurance Portability and Accountability Act (HIPAA) Guidelines. If patient is unable to comprehend or sign the ICF, patient's legally acceptable representative may sign the ICF; Exclusion Criteria Age < 18 years; Weight > 150 Kg / 330 pounds; Pregnant or lactating women; Female of childbearing potential, the patient must have a negative beta subunit hCG pregnancy test immediately prior to study entry (performed by urine or blood test, whichever is faster); Patient who has been operated at least once for the current NSTI infection and had a curative deep tissue debridement (diagnostic surgery is allowed to enter into the study); Known HIV infection with CD4 count < 200 cells/mm3 or < 14% of all lymphocytes; Diabetic patients with below ankle infection; Patients with overt peripheral vascular disease in the involved area - condition associated with ischemic ulcers and /or symptoms of inadequate vascular supply (e.g. intermittent claudication) where limb amputation is considered likely within 7 days; Current status of: a. Mean arterial pressure < 50 mmHg and/or systolic blood pressure < 70 mmHg despite treatment with vasopressors and/or 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 > 3) or d. thrombocytopenia (platelet count < 20,000) that does not partially correct with administration of appropriate factors, or e. likely severe neurological impairment secondary to cardiac arrest. Patients with cardiac arrest requiring cardiopulmonary resuscitation within the past 30 days; Patient is not expected to survive 30 days because of underlying medical condition, such as poorly controlled neoplasm (e.g. Stage III or IV cancer); Any concurrent medical condition, which in the opinion of the investigator, may compromise their safety or the objectives of the study or the patient will not benefit from treatment, (e.g. end stage organ disease {CHF {NYHA class III-IV}, COPD {stage III-IV}, Liver dysfunction {Childs-Pugh class C}, Renal dysfunction {Dialysis}), immunosuppression, receiving or about to receive chemotherapy or known severe neutropenia < 1,000 cells/mm3; Patients with Necrotizing Soft Tissue Infection post intra-abdominal operation; Patient with burn wounds; Patient or patient's family are not committed to aggressive management of the patient's condition, or the combination of necrotizing skin infection and underlying illness makes it unlikely that life support will be maintained; Previous enrolment in an previous clinical trial involving investigational drug or a medical device within 30 days before provision of written informed consent for the study or within five half lives of the investigational drug, whichever is longer;

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AB103 0.25 mg/kg<br> | Drug: AB103<br>* AB103 0.25 mg/kg or 0.5 mg/kg administered as a single IV infusion<br>* Other names: p2TA;|
| Active Comparator: AB103 0.5 mg/kg<br> | Drug: AB103<br>* AB103 0.25 mg/kg or 0.5 mg/kg administered as a single IV infusion<br>* Other names: p2TA;|
| Placebo Comparator: Placebo<br>Normal saline (0.9% sodium chloride) | Drug: Placebo<br>* Normal saline (0.9% sodium chloride) administered as a single IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With One or More Adverse Events (AEs) During the Treatment Period | An AE is any untoward medical occurrence in a subject administered study drug and that does not necessarily have a causal relationship with the study drug. An AE could therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug. | 7 days | 
| Number of Subjects With One or More Serious Adverse Events (SAEs) | A serious adverse event (SAE) is an AE occurring during any study phase and at any dose of the study drug (AB103 or placebo) that fulfills one or more of the following criteria: Results in death Is life-threatening (i.e., the subject was, in the opinion of the Investigator, at immediate risk of death from the event as it occurred) Requires or prolongs hospitalization Results in persistent or significant disability or incapacity (i.e., the event causes a substantial disruption of a person's ability to conduct normal life functions) Is a congenital anomaly or birth defect, or Is an important and significant medical event. | 28 days | 
| Alanine Aminotransferase (ALT) | Screening ALT results, Day 7 ALT results, and change in ALT from screening to Day 7 | Screening and Day 7 | 
| Aspartate Aminotransferase (AST) | Screening AST results, Day 7 AST results, and change in AST from screening to Day 7 | Screening and Day 7 | 
| Alkaline Phosphatase (ALP) | Screening ALP results, Day 7 ALP results, and change in ALP from screening to Day 7 | Screening and Day 7 | 
| Total Bilirubin (Tbili) | Screening Tbili results, Day 7 Tbili results, and change in Tbili from screening to Day 7 | Screening and Day 7 | 
| Serum Creatinine (sCr) | Screening sCr results, Day 7 sCr results, and change in sCr from screening to Day 7 | Screening and Day 7 | 
| Albumin (Alb) | Screening Alb results, Day 7 Alb results, and change in Alb from screening to Day 7 | Screening and Day 7 | 
| Hemoglobin (Hgb) | Screening Hgb results, Day 7 Hgb results, and change in Hgb from screening to Day 7 | Screening and Day 7 | 
| Total White Blood Cell (WBC) Count | Screening WBC results, Day 7 WBC results, and change in WBC from screening to Day 7 | Screening and Day 7 | 
| Platelet (PLT) Count | Screening PLT results, Day 7 PLT results, and change in PLT from screening to Day 7 | Screening and Day 7 | 
| International Normalized Ratio (INR) | Screening INR results, Day 7 INR results, and change in INR from screening to Day 7. In general, the higher the INR value, the longer it takes for blood to form a clot. | Screening and Day 7 | 
| QT Interval With Fridericia's Correction (QTcF) | Pre-dose QTcF, post-dose QTcF, change in QTcF from pre-dose to post-dose | Pre-dose and up to 24 hours post-dose | 
| Categorical Change in QTcF | Number and percentage of patients with a change in QTcF of > 30 msec; number and percentage of patients with a change in QTcF of > 60 msec | Pre-dose and up to 24 hours post-dose | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) | Area under the plasma concentration versus time curve (AUC) from time zero to infinity following a single dose of study drug, obtained by noncompartmental methods. It is an integrated measure of study drug plasma exposure. | Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug. | 
| Maximum Plasma Concentration (Cmax) | Maximum plasma concentration (observed) | Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug. | 
| Apparent Terminal Plasma Half-life (T1/2) | Apparent terminal plasma half-life (T1/2) is the amount of time for plasma concentrations to decline by 50%. | Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug. | 
| Clearance (CL) | Clearance (CL) is the volume of plasma completely cleared of drug per unit of time. | Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug. | 
| Apparent Volume of Distribution Under Steady State Conditions (Vss) | Apparent volume of distribution under steady state conditions (Vss) based on drug concentration in plasma | Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-reactive Protein (CRP) | Screening CRP results, Day 7 CRP results, and change in CRP from screening to Day 7 | Screening and Day 7 | 
| Day 14 Sequential Organ Failure Assessment (SOFA) Score | Day 14 SOFA score is the sum of individual SOFA score components at Day 14. Results include last observation carried forward (LOCF) imputation for missing values. SOFA total scores range from 0 to 24, with higher scores reflecting a worse clinical status or outcome. A SOFA total score of 0 or 1 reflects resolution of organ dysfunction/failure. | 14 days | 
| Day 14 Sequential Organ Failure Assessment (SOFA) Score Less Than or Equal to 1 | Number and percentage of patients with Day 14 Sequential Organ Failure Assessment (SOFA) score less than or equal to 1. SOFA total scores range from 0 to 24, with higher scores reflecting a worse clinical status or outcome. A SOFA total score of 0 or 1 reflects resolution of organ dysfunction/failure. | 14 days | 
| Hospital Length of Stay (LOS) | The duration of hospital stay over the 28-day study period. | 28 days | 
| Intensive Care Unit-free Days (ICU-free Days) | The number of intensive care unit-free days (ICU-free days) | 28 days | 
| Ventilator-free Days | The number of ventilator-free days (days without ventilator use) | 28 days |