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

NCT ID: NCT02469857

Last Updated: 2021-10-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 290 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-01
• Study Completion Date: 2019-10-18

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.

Conditions

Necrotizing Soft Tissue Infections; Necrotizing Fasciitis; Fournier's Gangrene

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

AB103 0.5 mg/kg

AB103 0.5 mg/kg, IV, single dose

Group Type: EXPERIMENTAL

AB103 0.5 mg/kg

Intervention Type: DRUG

NaCl 0.9%

NaCl 0.9%, IV, single dose

Group Type: PLACEBO_COMPARATOR

NaCl 0.9%

Intervention Type: OTHER

Interventions

AB103 0.5 mg/kg

Intervention Type: DRUG

NaCl 0.9%

Intervention Type: OTHER

Other Intervention Names

reltecimod; Normal saline

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;

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.

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Biomedical Advanced Research and Development Authority

FED

Sponsor Role: collaborator

Atox Bio Ltd

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Wayne M Dankner, MD

Role: STUDY_DIRECTOR

Atox Bio Ltd

Eileen M Bulger, MD

Role: PRINCIPAL_INVESTIGATOR

Harborview Injury Prevention and Research Center

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Maricopa Medical Center

Phoenix, Arizona, United States

Banner University Medical Center

Tucson, Arizona, United States

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

Loma Linda University Medical Center

Loma Linda, California, United States

Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center

Los Angeles, California, United States

University of California, Davis Medical Center

Sacramento, California, United States

UCSD Medical Center

San Diego, California, United States

UCH-Memorial Health System

Colorado Springs, Colorado, United States

University of Colorado Hospital

Denver, Colorado, United States

Yale New Haven Hospital

New Haven, Connecticut, United States

Washington Hospital Center

Washington D.C., District of Columbia, United States

UF Health Shands Hospital

Gainesville, Florida, United States

Ryder Trauma Center/Jackson Memorial Hospital

Miami, Florida, United States

Emory University at Grady Memorial Hospital

Atlanta, Georgia, United States

Augusta University Health

Augusta, Georgia, United States

University of Iowa Hospital and Clinics

Iowa City, Iowa, United States

University of Kentucky

Lexington, Kentucky, United States

Our Lady of the Lake Regional Medical Center

Baton Rouge, Louisiana, United States

Baton Rouge General Hospital

Baton Rouge, Louisiana, United States

LSU Health Science Center

New Orleans, Louisiana, United States

Maine Medical Center

Portland, Maine, United States

University of Maryland R Adams Cowley Shock Trauma Center

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Wayne State University-Detroit Receiving Hospital

Detroit, Michigan, United States

Henry Ford Health System

Detroit, Michigan, United States

Wayne State University-Sinai Grace Hospital

Detroit, Michigan, United States

Fairview Southdale Hospital

Edina, Minnesota, United States

Hennepin County Medical Center

Minneapolis, Minnesota, United States

University of Minnesota Medical Center-Fairview

Minneapolis, Minnesota, United States

University of Missouri

Columbia, Missouri, United States

St Louis University

St Louis, Missouri, United States

Cooper University Hospital

Camden, New Jersey, United States

Capital Health System, Inc.

Trenton, New Jersey, United States

Albany Medical Center

Albany, New York, United States

Erie County Medical Center-Affliate of SUNYat Buffalo

Buffalo, New York, United States

Staten Island University Hospital-Northwell Health

Staten Island, New York, United States

Carolinas Medical Center

Charlotte, North Carolina, United States

East Carolina University

Greenville, North Carolina, United States

University of Cincinnati Medical Center (UCMC)

Cincinnati, Ohio, United States

The MetroHealth System

Cleveland, Ohio, United States

The Ohio State University

Columbus, Ohio, United States

Wright State University & Premier Health Clinical Trials Research Alliance

Dayton, Ohio, United States

St Elizabeth Youngstown Hospital

Youngstown, Ohio, United States

Legacy Emanuel Hospital

Portland, Oregon, United States

Oregon Health and Science University

Portland, Oregon, United States

St. Luke's University Health Network

Bethlehem, Pennsylvania, United States

The Pennsylvania State University and The Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States

The Trauma Center at PENN

Philadelphia, Pennsylvania, United States

Thomas Jefferson University

Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Texas Tech University Health Sciences Center at El Paso

El Paso, Texas, United States

John Peter Smith Health Network

Fort Worth, Texas, United States

Baylor College of Medicine-Ben Taub Hospital

Houston, Texas, United States

University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

Scott and White Medical Center

Temple, Texas, United States

Harborview Medical Center

Seattle, Washington, United States

Medical College of Wisconsin-Froedtert Hospital

Milwaukee, Wisconsin, United States

Hộpital Estaing-CHU de Clermont-Ferrand

Clermont-Ferrand, , France

Hộpital Henri Mondor

Créteil, , France

Hôpital Bicêtre

Le Kremlin-Bicêtre, , France

Robert Salengro Hopital-CHRU Lille

Lille, , France

CHU de Limoges

Limoges, , France

Hôpital Edouard Herriot

Lyon, , France

CHRU Nancy, Hôpital Central

Nancy, , France

CHU de Nimes

Nîmes, , France

Hôpital de la Source, CHR Orleans

Orléans, , France

CHRU Bretonneau

Tours, , France

Countries

United States; France

References

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.

Reference Type: RESULT

PMID: 32657946 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

ATB-202

Identifier Type: -

Identifier Source: org_study_id