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

Necrotizing Fasciitis Clinical Trial

— ACCUTE  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02469857
• Other study ID #: ATB-202
• Status: Completed
• Phase: Phase 3
• Start date: December 1, 2015
• Est. completion date: October 18, 2019

Study information

• Verified date: October 2021
• Source: Atox Bio Ltd
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 290
• Est. completion date: October 18, 2019
• Est. primary completion date: August 18, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Communicable Diseases
• Fasciitis
• Fasciitis, Necrotizing
• Fournier Gangrene
• Fournier's Gangrene
• Gangrene
• Infections
• Necrotizing Fasciitis
• Necrotizing Soft Tissue Infections
• Soft Tissue Infections

Intervention

Drug:
• AB103 0.5 mg/kg

Other:
• NaCl 0.9%

Locations

Country	Name	City	State
France	H?pital Estaing-CHU de Clermont-Ferrand	Clermont-Ferrand
France	H?pital 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
United States	Albany Medical Center	Albany	New York
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University at Grady Memorial Hospital	Atlanta	Georgia
United States	Augusta University Health	Augusta	Georgia
United States	University of Maryland R Adams Cowley Shock Trauma Center	Baltimore	Maryland
United States	Baton Rouge General Hospital	Baton Rouge	Louisiana
United States	Our Lady of the Lake Regional Medical Center	Baton Rouge	Louisiana
United States	St. Luke's University Health Network	Bethlehem	Pennsylvania
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Erie County Medical Center-Affliate of SUNYat Buffalo	Buffalo	New York
United States	Cooper University Hospital	Camden	New Jersey
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	University of Cincinnati Medical Center (UCMC)	Cincinnati	Ohio
United States	The MetroHealth System	Cleveland	Ohio
United States	UCH-Memorial Health System	Colorado Springs	Colorado
United States	University of Missouri	Columbia	Missouri
United States	The Ohio State University	Columbus	Ohio
United States	Wright State University & Premier Health Clinical Trials Research Alliance	Dayton	Ohio
United States	University of Colorado Hospital	Denver	Colorado
United States	Henry Ford Health System	Detroit	Michigan
United States	Wayne State University-Detroit Receiving Hospital	Detroit	Michigan
United States	Wayne State University-Sinai Grace Hospital	Detroit	Michigan
United States	Fairview Southdale Hospital	Edina	Minnesota
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	UF Health Shands Hospital	Gainesville	Florida
United States	East Carolina University	Greenville	North Carolina
United States	The Pennsylvania State University and The Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Baylor College of Medicine-Ben Taub Hospital	Houston	Texas
United States	University of Iowa Hospital and Clinics	Iowa City	Iowa
United States	University of Kentucky	Lexington	Kentucky
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	Ryder Trauma Center/Jackson Memorial Hospital	Miami	Florida
United States	Medical College of Wisconsin-Froedtert Hospital	Milwaukee	Wisconsin
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale New Haven Hospital	New Haven	Connecticut
United States	LSU Health Science Center	New Orleans	Louisiana
United States	The Trauma Center at PENN	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Maricopa Medical Center	Phoenix	Arizona
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Hospital	Portland	Oregon
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health and Science University	Portland	Oregon
United States	University of California, Davis Medical Center	Sacramento	California
United States	St Louis University	Saint Louis	Missouri
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	UCSD Medical Center	San Diego	California
United States	Harborview Medical Center	Seattle	Washington
United States	Staten Island University Hospital-Northwell Health	Staten Island	New York
United States	Scott and White Medical Center	Temple	Texas
United States	Capital Health System, Inc.	Trenton	New Jersey
United States	Banner University Medical Center	Tucson	Arizona
United States	Washington Hospital Center	Washington	District of Columbia
United States	St Elizabeth Youngstown Hospital	Youngstown	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Atox Bio Ltd	Biomedical Advanced Research and Development Authority

Countries where clinical trial is conducted

United States,  France, 

References & Publications (1)

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 Infec — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Deaths From Day 0 Through Day 90	The number of deaths occurring from Study Day 0 through Study Day 90	90 days
Other	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)
Other	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
Other	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)
Other	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
Other	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)
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	Number of Patients With One or More Secondary Infections	Number of Patients with One or More Secondary Infections During the Study	28 days
Secondary	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
Secondary	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
Secondary	Ventilator-free Days	Ventilator-free days refers to the number of days a patient was not on a ventilator through Day 28.	28 days
Secondary	Vasopressor-free Days	Vasopressor-free days refers to the number of days a patient did not receive a vasopressor through Day 28.	28 days
Secondary	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
Secondary	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