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

Phase 3

Completed

Conditions: Fournier's Gangrene
Necrotizing Fasciitis
Necrotizing Soft Tissue Infections

Interventions: Drug: AB103 0.5 mg/kg
Other: NaCl 0.9%

Registration Number: NCT02469857

Lead Sponsor: Atox Bio Ltd

Brief Summary: The purpose of this study is to determine whether AB103 is safe and effective in the treatment of patients with necrotizing soft tissue infections (NSTI) receiving standard of care therapy.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 290

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AB103 0.5 mg/kg	AB103 0.5 mg/kg	AB103 0.5 mg/kg, IV, single dose
NaCl 0.9%	NaCl 0.9%	NaCl 0.9%, IV, single dose

Primary Outcome Measures

Name	Time	Method
Number of Patients Achieving Necrotizing Infections Clinical Composite Endpoint (NICCE)	28 days	NICCE was made up of the following 5 components, all of which had to be met to successfully achieve the primary outcome measure (i.e., a "responder"): (i) Alive at Day 28, (ii) ≤ 3 debridements through Day 14, (iii) No amputation performed after the first debridement, (iv) Day 14 modified Sequential Organ Failure Assessment (mSOFA) score ≤ 1, and (v) Reduction of ≥ 3 mSOFA score points between Baseline and Day 14. This analysis compared responders in the reltecimod group versus responders in the placebo group. Modified Sequential Organ Failure Assessment (mSOFA) total scores range from 0 to 20, with higher scores reflecting a worse clinical status or outcome. An mSOFA total score of 0 or 1 reflects resolution of organ dysfunction/failure.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With One or More Adverse Events (AEs)	28 days	Number of Patients With One or More Adverse Events (AEs). Serious Adverse Events (SAEs) are included in this outcome measure since SAEs are a subset of AEs.
Number of Patients With One or More Serious Adverse Events (SAEs)	28 days	Number of Patients with One or More Serious Adverse Events (SAEs) During the Study
Vasopressor-free Days	28 days	Vasopressor-free days refers to the number of days a patient did not receive a vasopressor through Day 28.
Number of Patients With One or More Secondary Infections	28 days	Number of Patients with One or More Secondary Infections During the Study
Number of Patients Achieving Day 14 Modified Sequential Organ Failure Assessment (mSOFA) Score of 0 or 1	14 days	Modified Sequential Organ Failure Assessment (mSOFA) total scores range from 0 to 20, with higher scores reflecting a worse clinical status or outcome. An mSOFA total score of 0 or 1 reflects resolution of organ dysfunction/failure.
Intensive Care Unit (ICU)-Free Days	28 days	ICU-free days refers to the number of days a patient did not spend time in the ICU through Day 28.
Ventilator-free Days	28 days	Ventilator-free days refers to the number of days a patient was not on a ventilator through Day 28.
Hospital Days	90 days or until end of follow up	Hospital days refers to the number of days a patient spent time in the hospital.
Number of Patients With a More Favorable or Less Favorable Hospital Discharge Location	90 days	Number of patients with more favorable discharge location (home or rehabilitation facility) or less favorable discharge location (skilled nursing facility, another acute care facility, death, other)

Trial Locations

Locations (71): Maricopa Medical Center
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Phoenix, Arizona, United States
University of Arkansas for Medical Sciences
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Little Rock, Arkansas, United States
Cooper University Hospital
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Camden, New Jersey, United States
Washington Hospital Center
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Washington, District of Columbia, United States
Capital Health System, Inc.
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Trenton, New Jersey, United States
The Ohio State University
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Columbus, Ohio, United States
Baylor College of Medicine-Ben Taub Hospital
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Houston, Texas, United States
Harborview Medical Center
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Seattle, Washington, United States
Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center
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Los Angeles, California, United States
UCH-Memorial Health System
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Colorado Springs, Colorado, United States
Yale New Haven Hospital
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New Haven, Connecticut, United States
University of Colorado Hospital
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Denver, Colorado, United States
Ryder Trauma Center/Jackson Memorial Hospital
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Miami, Florida, United States
Augusta University Health
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Augusta, Georgia, United States
University of Iowa Hospital and Clinics
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Iowa City, Iowa, United States
Our Lady of the Lake Regional Medical Center
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Baton Rouge, Louisiana, United States
LSU Health Science Center
🇺🇸
New Orleans, Louisiana, United States
Baton Rouge General Hospital
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Baton Rouge, Louisiana, United States
Brigham and Women's Hospital
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Boston, Massachusetts, United States
Massachusetts General Hospital
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Boston, Massachusetts, United States
Henry Ford Health System
🇺🇸
Detroit, Michigan, United States
University of Michigan
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Ann Arbor, Michigan, United States
Wayne State University-Detroit Receiving Hospital
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Detroit, Michigan, United States
Wayne State University-Sinai Grace Hospital
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Detroit, Michigan, United States
Fairview Southdale Hospital
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Edina, Minnesota, United States
Hennepin County Medical Center
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Minneapolis, Minnesota, United States
University of Minnesota Medical Center-Fairview
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Minneapolis, Minnesota, United States
Staten Island University Hospital-Northwell Health
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Staten Island, New York, United States
The MetroHealth System
🇺🇸
Cleveland, Ohio, United States
CHU de Limoges
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Limoges, France
CHRU Bretonneau
🇫🇷
Tours, France
Hôpital de la Source, CHR Orleans
🇫🇷
Orléans, France
University of Alabama at Birmingham
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Birmingham, Alabama, United States
Banner University Medical Center
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Tucson, Arizona, United States
University of Missouri
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Columbia, Missouri, United States
University of California, Davis Medical Center
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Sacramento, California, United States
UCSD Medical Center
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San Diego, California, United States
UF Health Shands Hospital
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Gainesville, Florida, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Erie County Medical Center-Affliate of SUNYat Buffalo
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Buffalo, New York, United States
The Trauma Center at PENN
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Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center
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Pittsburgh, Pennsylvania, United States
Texas Tech University Health Sciences Center at El Paso
🇺🇸
El Paso, Texas, United States
The Pennsylvania State University and The Milton S. Hershey Medical Center
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Hershey, Pennsylvania, United States
Emory University at Grady Memorial Hospital
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Atlanta, Georgia, United States
Maine Medical Center
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Portland, Maine, United States
University of Maryland R Adams Cowley Shock Trauma Center
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Baltimore, Maryland, United States
Hôpital Bicêtre
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Le Kremlin-Bicêtre, France
St Louis University
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Saint Louis, Missouri, United States
Hôpital Edouard Herriot
🇫🇷
Lyon, France
East Carolina University
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Greenville, North Carolina, United States
St Elizabeth Youngstown Hospital
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Youngstown, Ohio, United States
University of Cincinnati Medical Center (UCMC)
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Cincinnati, Ohio, United States
Albany Medical Center
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Albany, New York, United States
Vanderbilt University Medical Center
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Nashville, Tennessee, United States
Carolinas Medical Center
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Charlotte, North Carolina, United States
St. Luke's University Health Network
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Bethlehem, Pennsylvania, United States
Medical College of Wisconsin-Froedtert Hospital
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Milwaukee, Wisconsin, United States
University of Texas Health Science Center at San Antonio
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San Antonio, Texas, United States
Hộpital Henri Mondor
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Créteil, France
CHU de Nimes
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Nîmes, France
Scott and White Medical Center
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Temple, Texas, United States
Hộpital Estaing-CHU de Clermont-Ferrand
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Clermont-Ferrand, France
Robert Salengro Hopital-CHRU Lille
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Lille, France
CHRU Nancy, Hôpital Central
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Nancy, France
University of Kentucky
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Lexington, Kentucky, United States
John Peter Smith Health Network
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Fort Worth, Texas, United States
Wright State University & Premier Health Clinical Trials Research Alliance
🇺🇸
Dayton, Ohio, United States
Loma Linda University Medical Center
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Loma Linda, California, United States
Legacy Emanuel Hospital
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Portland, Oregon, United States
Thomas Jefferson University
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Philadelphia, Pennsylvania, United States