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.
Brief Title
Phase III Efficacy and Safety Study of AB103 in the Treatment of Patients With Necrotizing Soft Tissue Infections
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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Necrotizing Soft Tissue Infections
Necrotizing Fasciitis
Fournier's Gangrene
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.
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.
Inclusion 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
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
Gender
All
Gender Based
false
Keywords
AB103
Necrotizing fasciitis
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
12 Years
NCT Id
NCT02469857
Org Class
Industry
Org Full Name
Atox Bio Ltd
Org Study Id
ATB-202
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
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)
Primary Outcomes
Outcome Description
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.
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.
Outcome Measure
Number of Patients Achieving Necrotizing Infections Clinical Composite Endpoint (NICCE)
Outcome Time Frame
28 days
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
28 days
Outcome Measure
Number of Patients With One or More Adverse Events (AEs)
Outcome Description
Number of Patients with One or More Serious Adverse Events (SAEs) During the Study
Outcome Time Frame
28 days
Outcome Measure
Number of Patients With One or More Serious Adverse Events (SAEs)
Outcome Description
Number of Patients with One or More Secondary Infections During the Study
Outcome Time Frame
28 days
Outcome Measure
Number of Patients With One or More Secondary Infections
Outcome Description
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.
Outcome Time Frame
14 days
Outcome Measure
Number of Patients Achieving Day 14 Modified Sequential Organ Failure Assessment (mSOFA) Score of 0 or 1
Outcome Description
ICU-free days refers to the number of days a patient did not spend time in the ICU through Day 28.
Outcome Time Frame
28 days
Outcome Measure
Intensive Care Unit (ICU)-Free Days
Outcome Description
Ventilator-free days refers to the number of days a patient was not on a ventilator through Day 28.
Outcome Time Frame
28 days
Outcome Measure
Ventilator-free Days
Outcome Description
Vasopressor-free days refers to the number of days a patient did not receive a vasopressor through Day 28.
Outcome Time Frame
28 days
Outcome Measure
Vasopressor-free Days
Outcome Description
Hospital days refers to the number of days a patient spent time in the hospital.
Outcome Time Frame
90 days or until end of follow up
Outcome Measure
Hospital Days
Outcome Description
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)
Outcome Time Frame
90 days
Outcome Measure
Number of Patients With a More Favorable or Less Favorable Hospital Discharge Location
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
12
Investigators
Investigator Type
Principal Investigator
Investigator Name
Vance Smith
Investigator Email
vsmith@montefiore.org
Investigator Phone