Clinical trial NCT01417780: Evaluation of Safety, PK and Immunomodulatory Effects of AB103 in Necrotizing Soft Tissue Infections Patients
Official title: Evaluation of Safety, Pharmacokinetics and Immunomodulatory Effects of AB103, a CD28 Co-stimulatory Receptor Antagonist, in Patients Diagnosed With Necrotizing Soft Tissue Infections
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Necrotizing Soft Tissue Infections
Lead sponsor: Atox Bio Ltd
Sponsor class: INDUSTRY
First posted: 2011-08-16
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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:

1. Clinical status domain
2. Pharmacoeconomics domain
3. Systemic and local inflammatory biomarker domain

Eligibility criteria: 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;

Primary outcomes:
measure: Number of Subjects With One or More Adverse Events (AEs) During the Treatment Period
timeFrame: 7 days
measure: Number of Subjects With One or More Serious Adverse Events (SAEs)
timeFrame: 28 days
measure: Alanine Aminotransferase (ALT)
timeFrame: Screening and Day 7
measure: Aspartate Aminotransferase (AST)
timeFrame: Screening and Day 7
measure: Alkaline Phosphatase (ALP)
timeFrame: Screening and Day 7
measure: Total Bilirubin (Tbili)
timeFrame: Screening and Day 7
measure: Serum Creatinine (sCr)
timeFrame: Screening and Day 7
measure: Albumin (Alb)
timeFrame: Screening and Day 7
measure: Hemoglobin (Hgb)
timeFrame: Screening and Day 7
measure: Total White Blood Cell (WBC) Count
timeFrame: Screening and Day 7
measure: Platelet (PLT) Count
timeFrame: Screening and Day 7
measure: International Normalized Ratio (INR)
timeFrame: Screening and Day 7
measure: QT Interval With Fridericia's Correction (QTcF)
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Categorical Change in QTcF
timeFrame: Pre-dose and up to 24 hours post-dose
measure: Area Under the Plasma Concentration Versus Time Curve (AUC)
timeFrame: 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.
measure: Maximum Plasma Concentration (Cmax)
timeFrame: 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.
measure: Apparent Terminal Plasma Half-life (T1/2)
timeFrame: 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.
measure: Clearance (CL)
timeFrame: 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.
measure: Apparent Volume of Distribution Under Steady State Conditions (Vss)
timeFrame: 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 outcomes:
measure: C-reactive Protein (CRP)
timeFrame: Screening and Day 7
measure: Day 14 Sequential Organ Failure Assessment (SOFA) Score
timeFrame: 14 days
measure: Day 14 Sequential Organ Failure Assessment (SOFA) Score Less Than or Equal to 1
timeFrame: 14 days
measure: Hospital Length of Stay (LOS)
timeFrame: 28 days
measure: Intensive Care Unit-free Days (ICU-free Days)
timeFrame: 28 days
measure: Ventilator-free Days
timeFrame: 28 days
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California Los Angeles
state: California
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
Study officials:
References:
citation: Bulger EM, Maier RV, Sperry J, Joshi M, Henry S, Moore FA, Moldawer LL, Demetriades D, Talving P, Schreiber M, Ham B, Cohen M, Opal S, Segalovich I, Maislin G, Kaempfer R, Shirvan A. A Novel Drug for Treatment of Necrotizing Soft-Tissue Infections: A Randomized Clinical Trial. JAMA Surg. 2014 Jun;149(6):528-36. doi: 10.1001/jamasurg.2013.4841.
citation: Bulger EM, Maislin G, Dankner W, May A, Edgar R, Shirvan A. Critical Care Medicine, January 2018,46(1):327. Abstract 682: Early Plasma Cytokine Levels Correlate With Outcome in Necrotizing Soft Tissue Infections. https://journals.lww.com/ccmjournal/Citation/2018/01001/682