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

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)

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.

Study Overview

• Status: Completed
• Conditions: Necrotizing Fasciitis; Necrotizing Soft Tissue Infections; Fournier's Gangrene
• Intervention / Treatment: Drug: AB103 0.5 mg/kg; Other: NaCl 0.9%

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.

• Study Type: Interventional
• Enrollment (Actual): 290
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Clermont-Ferrand, France
    • Hộpital Estaing-CHU de Clermont-Ferrand
  • Créteil, France
    • Hopital Henri Mondor
  • Le Kremlin-Bicêtre, France
    • Hôpital Bicêtre
  • Lille, France
    • Robert Salengro Hopital-CHRU Lille
  • Limoges, France
    • CHU de Limoges
  • Lyon, France
    • Hopital Edouard Herriot
  • Nancy, France
    • CHRU Nancy, Hopital central
  • Nîmes, France
    • CHU de Nîmes
  • Orléans, France
    • Hôpital de La Source, CHR Orléans
  • Tours, France
    • CHRU Bretonneau
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85008
      • Maricopa Medical Center
    • Tucson, Arizona, United States, 24857
      • Banner University Medical Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Los Angeles, California, United States, 90502
      • Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center
    • Sacramento, California, United States, 95817
      • University of California, Davis Medical Center
    • San Diego, California, United States, 92103
      • UCSD Medical Center
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • UCH-Memorial Health System
    • Denver, Colorado, United States, 80045
      • University of Colorado Hospital
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale New Haven Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • UF Health Shands Hospital
    • Miami, Florida, United States, 33136
      • Ryder Trauma Center/Jackson Memorial Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University at Grady Memorial Hospital
    • Augusta, Georgia, United States, 30912
      • Augusta University Health
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospital and Clinics
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University Of Kentucky
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Our Lady of the Lake Regional Medical Center
    • Baton Rouge, Louisiana, United States, 70809
      • Baton Rouge General Hospital
    • New Orleans, Louisiana, United States, 70112
      • LSU Health Science Center
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland R Adams Cowley Shock Trauma Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Detroit, Michigan, United States, 48201
      • Wayne State University-Detroit Receiving Hospital
    • Detroit, Michigan, United States, 48235
      • Wayne State University-Sinai Grace Hospital
  • Minnesota
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center-Fairview
  • Missouri
    • Columbia, Missouri, United States, 65211
      • University of Missouri
    • Saint Louis, Missouri, United States, 63103
      • St Louis University
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper University Hospital
    • Trenton, New Jersey, United States, 98638
      • Capital Health System, Inc.
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Buffalo, New York, United States, 14215
      • Erie County Medical Center-Affliate of SUNYat Buffalo
    • Staten Island, New York, United States, 10305
      • Staten Island University Hospital-Northwell Health
  • North Carolina
    • Charlotte, North Carolina, United States, 28208
      • Carolinas Medical Center
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center (UCMC)
    • Cleveland, Ohio, United States, 44109
      • The MetroHealth System
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
    • Dayton, Ohio, United States, 45409
      • Wright State University & Premier Health Clinical Trials Research Alliance
    • Youngstown, Ohio, United States, 44501
      • St Elizabeth Youngstown Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • St. Luke's University Health Network
    • Hershey, Pennsylvania, United States, 17033
      • The Pennsylvania State University and The Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19104
      • The Trauma Center at PENN
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • El Paso, Texas, United States, 79905
      • Texas Tech University Health Sciences Center at El Paso
    • Fort Worth, Texas, United States, 76104
      • John Peter Smith Health Network
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine-Ben Taub Hospital
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • Temple, Texas, United States, 76502
      • Scott and White Medical Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin-Froedtert Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AB103 0.5 mg/kg; AB103 0.5 mg/kg, IV, single dose	Drug: AB103 0.5 mg/kg; Other Names: reltecimod
Placebo Comparator: NaCl 0.9%; NaCl 0.9%, IV, single dose	Other: NaCl 0.9%; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Achieving Necrotizing Infections Clinical Composite Endpoint (NICCE)	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.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With One or More Adverse Events (AEs)	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.	28 days
Number of Patients With One or More Serious Adverse Events (SAEs)	Number of Patients with One or More Serious Adverse Events (SAEs) During the Study	28 days
Number of Patients With One or More Secondary Infections	Number of Patients with One or More Secondary Infections During the Study	28 days
Number of Patients Achieving Day 14 Modified Sequential Organ Failure Assessment (mSOFA) Score of 0 or 1	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.	14 days
Intensive Care Unit (ICU)-Free Days	ICU-free days refers to the number of days a patient did not spend time in the ICU through Day 28.	28 days
Ventilator-free Days	Ventilator-free days refers to the number of days a patient was not on a ventilator through Day 28.	28 days
Vasopressor-free Days	Vasopressor-free days refers to the number of days a patient did not receive a vasopressor through Day 28.	28 days
Hospital Days	Hospital days refers to the number of days a patient spent time in the hospital.	90 days or until end of follow up
Number of Patients With a More Favorable or Less Favorable Hospital Discharge Location	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)	90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Deaths From Day 0 Through Day 90	The number of deaths occurring from Study Day 0 through Study Day 90	90 days
Number of Deaths After Day 14 Through Day 90	Number of deaths after Study Day 14 through Study Day 90	76 days (after Day 14 through Day 90)
Number of Deaths From Day 0 Through Day 90 Among Patients With a Screening mSOFA Score of at Least 5	Number and percentage of patients with a Screening mSOFA score of at least 5 who were alive on Study Day 0 and subsequently died through Study Day 90.	90 days
Number of Deaths After Day 14 Through Day 90 Among Patients With a Screening mSOFA Score of at Least 5	Number and percentage of patients with a Screening mSOFA score of at least 5 who were alive on Study Day 14 and subsequently died through Study Day 90.	76 days (after Day 14 through Day 90)
Number of Deaths From Day 0 Through Day 90 Among Patients With Baseline Cardiovascular Failure (Shock)	Number and percentage of patients with baseline cardiovascular failure (shock) who died through Study Day 90.	90 days
Number of Deaths After Day 14 Through Day 90 Among Patients With Baseline Cardiovascular Failure (Shock)	Number and percentage of patients with baseline cardiovascular failure (shock) who were alive on Study Day 14 and subsequently died through Study Day 90.	76 days (after Day 14 through Day 90)
Number of Patients With a Screening Modified Sequential Organ Failure Assessment (mSOFA) Score of at Least 5 Who Achieved NICCE	NICCE was made up of the following 5 components, all of which had to be met to successfully achieve the primary outcome measure: (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. 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.	28 days
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	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.	14 days
Number of Patients With Baseline Cardiovascular Failure (Shock) Who Achieved NICCE	NICCE was made up of the following 5 components, all of which had to be met to successfully achieve the primary outcome measure: (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.	28 days
Number of Patients With Baseline Cardiovascular Failure (Shock) Who Achieved Day 14 Modified Sequential Organ Failure Assessment (mSOFA) Score of 0 or 1	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.	14 days

Collaborators and Investigators

• Sponsor: Atox Bio Ltd
• Collaborators: Biomedical Advanced Research and Development Authority
• Investigators: Study Director: Wayne M Dankner, MD, Atox Bio Ltd; Principal Investigator: Eileen M Bulger, MD, Harborview Injury Prevention and Research Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): August 18, 2019
• Study Completion (Actual): October 18, 2019

Study Registration Dates

• First Submitted: June 6, 2015
• First Submitted That Met QC Criteria: June 11, 2015
• First Posted (Estimate): June 12, 2015

Study Record Updates

• Last Update Posted (Actual): October 5, 2021
• Last Update Submitted That Met QC Criteria: October 2, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Necrotizing fasciitis; AB103
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Disease Attributes; Musculoskeletal Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Communicable Diseases; Soft Tissue Infections; Gangrene; Fasciitis; Fournier Gangrene; Fasciitis, Necrotizing
• Other Study ID Numbers: ATB-202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No