Clinical trial NCT02469857: Phase III Efficacy and Safety Study of AB103 in the Treatment of Patients With Necrotizing Soft Tissue Infections
Official title: Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Study of AB103 as Compared to Placebo in Patients With Necrotizing Soft Tissue Infections. ACCUTE (AB103 Clinical Composite Endpoint Study in Necrotizing Soft Tissue Infections)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Necrotizing Soft Tissue Infections
Necrotizing Fasciitis
Fournier's Gangrene
Keywords: AB103
Necrotizing fasciitis
Lead sponsor: Atox Bio Ltd
Sponsor class: INDUSTRY
Collaborators: name: Biomedical Advanced Research and Development Authority
First posted: 2015-06-12
Enrollment: 290
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Surgical confirmation of NSTI by attending surgeon;
2. 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;
3. 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);
4. If a woman is of childbearing potential, she must consistently use an acceptable method of contraception from baseline through Day 28;
5. 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.
6. 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:

1. BMI\>51;
2. Patient who has been operated at least once for the current NSTI infection and had a curative deep tissue debridement;
3. Patients with overt peripheral vascular disease in the involved area ;
4. Diabetic patients with peripheral vascular disease who present with below the ankle infection;
5. Removed deep vein thrombosis (DVT) in area of NSTI as an exclusion criteria
6. Patient with burn wounds;
7. 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;
8. Chronic neurological impairment that leads to a neuro mSOFA component ≥2;
9. Recent cerebrovascular accident in the last 3 months;
10. Patients with cardiac arrest requiring cardiopulmonary resuscitation within the past 30 days;
11. Patient is not expected to survive throughout 28 days of study due to underlying medical condition, such as poorly controlled neoplasm;
12. Patient or patient's family are not committed to aggressive management of the patient's condition;
13. 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;
14. Known HIV infection with CD4 (cluster of differentiation 4) count \< 200 cells/mm3 or \< 14% of all lymphocytes;
15. Patients with known chronic kidney disease (documented pre-illness creatinine value(s) ≥2.0) or patients receiving renal replacement therapy for chronic kidney disease;
16. 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;
17. Pregnant or lactating women;
18. Previous enrollment in a clinical trial involving investigational drug or a medical device within 30 days;
19. Previous enrollment in this protocol, ATB-202 or the Phase 2 trial of AB103, ATB-201.

Primary outcomes:
measure: Number of Patients Achieving Necrotizing Infections Clinical Composite Endpoint (NICCE)
timeFrame: 28 days
Secondary outcomes:
measure: Number of Patients With One or More Adverse Events (AEs)
timeFrame: 28 days
measure: Number of Patients With One or More Serious Adverse Events (SAEs)
timeFrame: 28 days
measure: Number of Patients With One or More Secondary Infections
timeFrame: 28 days
measure: Number of Patients Achieving Day 14 Modified Sequential Organ Failure Assessment (mSOFA) Score of 0 or 1
timeFrame: 14 days
measure: Intensive Care Unit (ICU)-Free Days
timeFrame: 28 days
measure: Ventilator-free Days
timeFrame: 28 days
measure: Vasopressor-free Days
timeFrame: 28 days
measure: Hospital Days
timeFrame: 90 days or until end of follow up
measure: Number of Patients With a More Favorable or Less Favorable Hospital Discharge Location
timeFrame: 90 days
Other outcomes:
measure: Number of Deaths From Day 0 Through Day 90
timeFrame: 90 days
measure: Number of Deaths After Day 14 Through Day 90
timeFrame: 76 days (after Day 14 through Day 90)
measure: Number of Deaths From Day 0 Through Day 90 Among Patients With a Screening mSOFA Score of at Least 5
timeFrame: 90 days
measure: Number of Deaths After Day 14 Through Day 90 Among Patients With a Screening mSOFA Score of at Least 5
timeFrame: 76 days (after Day 14 through Day 90)
measure: Number of Deaths From Day 0 Through Day 90 Among Patients With Baseline Cardiovascular Failure (Shock)
timeFrame: 90 days
measure: Number of Deaths After Day 14 Through Day 90 Among Patients With Baseline Cardiovascular Failure (Shock)
timeFrame: 76 days (after Day 14 through Day 90)
measure: Number of Patients With a Screening Modified Sequential Organ Failure Assessment (mSOFA) Score of at Least 5 Who Achieved NICCE
timeFrame: 28 days
measure: Number of Patients With a Screening mSOFA Score of at Least 5 Who Achieved Day 14 Modified Sequential Organ Failure Assessment (mSOFA) Score of 0 or 1
timeFrame: 14 days
measure: Number of Patients With Baseline Cardiovascular Failure (Shock) Who Achieved NICCE
timeFrame: 28 days
measure: Number of Patients With Baseline Cardiovascular Failure (Shock) Who Achieved Day 14 Modified Sequential Organ Failure Assessment (mSOFA) Score of 0 or 1
timeFrame: 14 days
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Maricopa Medical Center
state: Arizona
city: Tucson
country: United States
facility: Banner University Medical Center
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Los Angeles
country: United States
facility: Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center
state: California
city: Sacramento
country: United States
facility: University of California, Davis Medical Center
state: California
city: San Diego
country: United States
facility: UCSD Medical Center
state: California
city: Colorado Springs
country: United States
facility: UCH-Memorial Health System
state: Colorado
city: Denver
country: United States
facility: University of Colorado Hospital
state: Colorado
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Washington
country: United States
facility: Washington Hospital Center
state: District of Columbia
city: Gainesville
country: United States
facility: UF Health Shands Hospital
state: Florida
city: Miami
country: United States
facility: Ryder Trauma Center/Jackson Memorial Hospital
state: Florida
city: Atlanta
country: United States
facility: Emory University at Grady Memorial Hospital
state: Georgia
city: Augusta
country: United States
facility: Augusta University Health
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baton Rouge
country: United States
facility: Our Lady of the Lake Regional Medical Center
state: Louisiana
city: Baton Rouge
country: United States
facility: Baton Rouge General Hospital
state: Louisiana
city: New Orleans
country: United States
facility: LSU Health Science Center
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: University of Maryland R Adams Cowley Shock Trauma Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Wayne State University-Detroit Receiving Hospital
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Detroit
country: United States
facility: Wayne State University-Sinai Grace Hospital
state: Michigan
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center-Fairview
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
city: Saint Louis
country: United States
facility: St Louis University
state: Missouri
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: Trenton
country: United States
facility: Capital Health System, Inc.
state: New Jersey
city: Albany
country: United States
facility: Albany Medical Center
state: New York
city: Buffalo
country: United States
facility: Erie County Medical Center-Affliate of SUNYat Buffalo
state: New York
city: Staten Island
country: United States
facility: Staten Island University Hospital-Northwell Health
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center (UCMC)
state: Ohio
city: Cleveland
country: United States
facility: The MetroHealth System
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Dayton
country: United States
facility: Wright State University & Premier Health Clinical Trials Research Alliance
state: Ohio
city: Youngstown
country: United States
facility: St Elizabeth Youngstown Hospital
state: Ohio
city: Portland
country: United States
facility: Legacy Emanuel Hospital
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Bethlehem
country: United States
facility: St. Luke's University Health Network
state: Pennsylvania
city: Hershey
country: United States
facility: The Pennsylvania State University and The Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: The Trauma Center at PENN
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: El Paso
country: United States
facility: Texas Tech University Health Sciences Center at El Paso
state: Texas
city: Fort Worth
country: United States
facility: John Peter Smith Health Network
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine-Ben Taub Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Temple
country: United States
facility: Scott and White Medical Center
state: Texas
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin-Froedtert Hospital
state: Wisconsin
city: Clermont-Ferrand
country: France
facility: Hộpital Estaing-CHU de Clermont-Ferrand
city: Créteil
country: France
facility: Hộpital Henri Mondor
city: Le Kremlin-Bicêtre
country: France
facility: Hôpital Bicêtre
city: Lille
country: France
facility: Robert Salengro Hopital-CHRU Lille
city: Limoges
country: France
facility: CHU de Limoges
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Nancy
country: France
facility: CHRU Nancy, Hôpital Central
city: Nîmes
country: France
facility: CHU de Nimes
city: Orléans
country: France
facility: Hôpital de la Source, CHR Orleans
city: Tours
country: France
facility: CHRU Bretonneau
Study officials:
affiliation: Atox Bio Ltd
name: Wayne M Dankner, MD
role: STUDY_DIRECTOR
affiliation: Harborview Injury Prevention and Research Center
name: Eileen M Bulger, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bulger EM, May AK, Robinson BRH, Evans DC, Henry S, Green JM, Toschlog E, Sperry JL, Fagenholz P, Martin ND, Dankner WM, Maislin G, Wilfret D, Bernard AC; ACCUTE Study Investigators. A Novel Immune Modulator for Patients With Necrotizing Soft Tissue Infections (NSTI): Results of a Multicenter, Phase 3 Randomized Controlled Trial of Reltecimod (AB 103). Ann Surg. 2020 Sep 1;272(3):469-478. doi: 10.1097/SLA.0000000000004102.