Necrotizing Soft Tissue Infections
Conditions
Brief summary
A study to evaluate the safety and pharmacokinetics profile of different doses of AB103 administered to patients diagnosed with Necrotizing Soft Tissue Infections that are scheduled for an urgent surgical intervention as part of their standard of care.
Detailed description
A study to evaluate the safety and pharmacokinetics profile of different doses of AB103 administered to patients diagnosed with Necrotizing Soft Tissue Infections that are scheduled for an urgent surgical intervention as part of their standard of care. The primary study hypothesis is that AB-103 can be administered safely to the patients presenting with Necrotizing Soft Tissue Infections. Secondary endpoints are efficacy by exploratory descriptive analyses of specific efficacy endpoints from three outcome domains to demonstrate treatment benefit of AB103 in comparison to placebo in patients with Necrotizing Soft Tissue Infections. The efficacy domains are: 1. Clinical status domain 2. Pharmacoeconomics domain 3. Systemic and local inflammatory biomarker domain
Interventions
DRUGAB103
AB103 0.25 mg/kg or 0.5 mg/kg administered as a single IV infusion
DRUGPlacebo
Normal saline (0.9% sodium chloride) administered as a single IV infusion
Sponsors
Atox Bio Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of NSTI due to bacterial infection (Necrotizing Fasciitis, Group A streptococcal infection or non group A streptococcal infection, Fournier's gangrene, Bacterial synergistic gangrene, Synergistic Necrotizing Cellulitis, Clostridial gas gangrene/ myonecrosis) that may be supported by specific signs and symptoms, e.g. tense edema outside area of compromised skin, pain disproportionate to appearance, skin discoloration, ecchymosis, blisters/bullae, necrosis, tense edema, crepitus and/or subcutaneous gas AND a decision for urgent surgical exploration and debridement; * Patient who did not receive the study drug prior to the surgery need to have a definite diagnosis of NSTI confirmed surgically (e.g. presence of necrotic tissue, thrombosed vessels in the subcutaneous tissue, lack of bleeding and dishwater (cloudy, thin, gray) fluid) in order to get the drug during or after operation; * IV drug administration within 6 hours from the clinical diagnosis and from the documented decision to have an urgent surgical exploration and debridement; * Signed and dated ICF as defined by the IRB and, if applicable, California Bill of Rights. By signing the ICF, the patient agrees to release any medical records pursuant to current Health Insurance Portability and Accountability Act (HIPAA) Guidelines. If patient is unable to comprehend or sign the ICF, patient's legally acceptable representative may sign the ICF;
Exclusion criteria
* Age \< 18 years; * Weight \> 150 Kg / 330 pounds; * Pregnant or lactating women; Female of childbearing potential, the patient must have a negative beta subunit hCG pregnancy test immediately prior to study entry (performed by urine or blood test, whichever is faster); * Patient who has been operated at least once for the current NSTI infection and had a curative deep tissue debridement (diagnostic surgery is allowed to enter into the study); * Known HIV infection with CD4 count \< 200 cells/mm3 or \< 14% of all lymphocytes; * Diabetic patients with below ankle infection; * Patients with overt peripheral vascular disease in the involved area - condition associated with ischemic ulcers and /or symptoms of inadequate vascular supply (e.g. intermittent claudication) where limb amputation is considered likely within 7 days; * Current status of: a. Mean arterial pressure \< 50 mmHg and/or systolic blood pressure \< 70 mmHg despite treatment with vasopressors and/or 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 \> 3) or d. thrombocytopenia (platelet count \< 20,000) that does not partially correct with administration of appropriate factors, or e. likely severe neurological impairment secondary to cardiac arrest. * Patients with cardiac arrest requiring cardiopulmonary resuscitation within the past 30 days; * Patient is not expected to survive 30 days because of underlying medical condition, such as poorly controlled neoplasm (e.g. Stage III or IV cancer); * Any concurrent medical condition, which in the opinion of the investigator, may compromise their safety or the objectives of the study or the patient will not benefit from treatment, (e.g. end stage organ disease {CHF {NYHA class III-IV}, COPD {stage III-IV}, Liver dysfunction {Childs-Pugh class C}, Renal dysfunction {Dialysis}), immunosuppression, receiving or about to receive chemotherapy or known severe neutropenia \< 1,000 cells/mm3; * Patients with Necrotizing Soft Tissue Infection post intra-abdominal operation; * Patient with burn wounds; * Patient or patient's family are not committed to aggressive management of the patient's condition, or the combination of necrotizing skin infection and underlying illness makes it unlikely that life support will be maintained; * Previous enrolment in an previous clinical trial involving investigational drug or a medical device within 30 days before provision of written informed consent for the study or within five half lives of the investigational drug, whichever is longer;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Volume of Distribution Under Steady State Conditions (Vss) | Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug. | Apparent volume of distribution under steady state conditions (Vss) based on drug concentration in plasma |
| QT Interval With Fridericia's Correction (QTcF) | Pre-dose and up to 24 hours post-dose | Pre-dose QTcF, post-dose QTcF, change in QTcF from pre-dose to post-dose |
| Categorical Change in QTcF | Pre-dose and up to 24 hours post-dose | Number and percentage of patients with a change in QTcF of \> 30 msec; number and percentage of patients with a change in QTcF of \> 60 msec |
| Area Under the Plasma Concentration Versus Time Curve (AUC) | Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug. | Area under the plasma concentration versus time curve (AUC) from time zero to infinity following a single dose of study drug, obtained by noncompartmental methods. It is an integrated measure of study drug plasma exposure. |
| Maximum Plasma Concentration (Cmax) | Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug. | Maximum plasma concentration (observed) |
| Apparent Terminal Plasma Half-life (T1/2) | Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug. | Apparent terminal plasma half-life (T1/2) is the amount of time for plasma concentrations to decline by 50%. |
| Clearance (CL) | Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug. | Clearance (CL) is the volume of plasma completely cleared of drug per unit of time. |
| Number of Subjects With One or More Adverse Events (AEs) During the Treatment Period | 7 days | An AE is any untoward medical occurrence in a subject administered study drug and that does not necessarily have a causal relationship with the study drug. An AE could therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug. |
| Number of Subjects With One or More Serious Adverse Events (SAEs) | 28 days | A serious adverse event (SAE) is an AE occurring during any study phase and at any dose of the study drug (AB103 or placebo) that fulfills one or more of the following criteria: * Results in death * Is life-threatening (i.e., the subject was, in the opinion of the Investigator, at immediate risk of death from the event as it occurred) * Requires or prolongs hospitalization * Results in persistent or significant disability or incapacity (i.e., the event causes a substantial disruption of a person's ability to conduct normal life functions) * Is a congenital anomaly or birth defect, or * Is an important and significant medical event. |
| Alanine Aminotransferase (ALT) | Screening and Day 7 | Screening ALT results, Day 7 ALT results, and change in ALT from screening to Day 7 |
| Aspartate Aminotransferase (AST) | Screening and Day 7 | Screening AST results, Day 7 AST results, and change in AST from screening to Day 7 |
| Alkaline Phosphatase (ALP) | Screening and Day 7 | Screening ALP results, Day 7 ALP results, and change in ALP from screening to Day 7 |
| Total Bilirubin (Tbili) | Screening and Day 7 | Screening Tbili results, Day 7 Tbili results, and change in Tbili from screening to Day 7 |
| Serum Creatinine (sCr) | Screening and Day 7 | Screening sCr results, Day 7 sCr results, and change in sCr from screening to Day 7 |
| Albumin (Alb) | Screening and Day 7 | Screening Alb results, Day 7 Alb results, and change in Alb from screening to Day 7 |
| Hemoglobin (Hgb) | Screening and Day 7 | Screening Hgb results, Day 7 Hgb results, and change in Hgb from screening to Day 7 |
| Total White Blood Cell (WBC) Count | Screening and Day 7 | Screening WBC results, Day 7 WBC results, and change in WBC from screening to Day 7 |
| Platelet (PLT) Count | Screening and Day 7 | Screening PLT results, Day 7 PLT results, and change in PLT from screening to Day 7 |
| International Normalized Ratio (INR) | Screening and Day 7 | Screening INR results, Day 7 INR results, and change in INR from screening to Day 7. In general, the higher the INR value, the longer it takes for blood to form a clot. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Day 14 Sequential Organ Failure Assessment (SOFA) Score | 14 days | Day 14 SOFA score is the sum of individual SOFA score components at Day 14. Results include last observation carried forward (LOCF) imputation for missing values. SOFA total scores range from 0 to 24, with higher scores reflecting a worse clinical status or outcome. A SOFA total score of 0 or 1 reflects resolution of organ dysfunction/failure. |
| Day 14 Sequential Organ Failure Assessment (SOFA) Score Less Than or Equal to 1 | 14 days | Number and percentage of patients with Day 14 Sequential Organ Failure Assessment (SOFA) score less than or equal to 1. SOFA total scores range from 0 to 24, with higher scores reflecting a worse clinical status or outcome. A SOFA total score of 0 or 1 reflects resolution of organ dysfunction/failure. |
| Hospital Length of Stay (LOS) | 28 days | The duration of hospital stay over the 28-day study period. |
| Intensive Care Unit-free Days (ICU-free Days) | 28 days | The number of intensive care unit-free days (ICU-free days) |
| Ventilator-free Days | 28 days | The number of ventilator-free days (days without ventilator use) |
| C-reactive Protein (CRP) | Screening and Day 7 | Screening CRP results, Day 7 CRP results, and change in CRP from screening to Day 7 |
Countries
United States
Participant flow
Recruitment details
This study was conducted by qualified investigators under the sponsorship of Atox Bio Ltd. at 7 trauma centers, of which 6 enrolled patients from December 2011 through August 2012.
Pre-assignment details
Of 43 randomized patients who received AB103 or placebo (intent-to-treat \[ITT\] population; safety analyses), 3 patients were excluded to form the modified intent-to-treat (mITT) population before unblinding due to protocol violations. Therefore, a total of 40 patients were included in the mITT efficacy analyses. With respect to any variable, the number of patients analyzed is the number of patients with non-missing data within the respective population.
Participants by arm
| Arm | Count |
|---|---|
| AB103 0.25 mg/kg AB103 0.25 mg/kg administered as a single IV infusion | 15 |
| AB103 0.5 mg/kg AB103 0.5 mg/kg administered as a single IV infusion | 15 |
| Placebo Normal saline (0.9% sodium chloride) administered as a single IV infusion | 10 |
| Total | 40 |
Baseline characteristics
| Characteristic | Total | AB103 0.25 mg/kg | AB103 0.5 mg/kg | Placebo |
|---|---|---|---|---|
| Acute Physiology And Chronic Health Evaluation II (APACHE II) Score | 8.3 units on a scale STANDARD_DEVIATION 4.7 | 7.5 units on a scale STANDARD_DEVIATION 5 | 8.3 units on a scale STANDARD_DEVIATION 4.5 | 9.6 units on a scale STANDARD_DEVIATION 4.7 |
| Age, Continuous | 50.9 years STANDARD_DEVIATION 15.2 | 46.3 years STANDARD_DEVIATION 13.6 | 50.1 years STANDARD_DEVIATION 15.2 | 52.5 years STANDARD_DEVIATION 20.4 |
| Body Mass Index (BMI) | 31.5 kg/m2 STANDARD_DEVIATION 8.2 | 31.0 kg/m2 STANDARD_DEVIATION 6.5 | 31.7 kg/m2 STANDARD_DEVIATION 9.7 | 29.9 kg/m2 STANDARD_DEVIATION 9.3 |
| Cardiovascular Organ Failure | 5 Participants | 1 Participants | 4 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 2 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants | 13 Participants | 14 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| NSTI Diagnosis Fournier Gangrene | 13 Participants | 5 Participants | 6 Participants | 2 Participants |
| NSTI Diagnosis Other NSTI | 27 Participants | 10 Participants | 9 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 35 Participants | 14 Participants | 14 Participants | 7 Participants |
| Sequential Organ Failure Assessment (SOFA) Score | 3.15 units on a scale STANDARD_DEVIATION 2.42 | 2.87 units on a scale STANDARD_DEVIATION 2.7 | 3.47 units on a scale STANDARD_DEVIATION 2.53 | 3.10 units on a scale STANDARD_DEVIATION 1.97 |
| Sex: Female, Male Female | 14 Participants | 4 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 26 Participants | 11 Participants | 9 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 15 | 1 / 17 | 2 / 11 |
| other Total, other adverse events | 14 / 15 | 16 / 17 | 9 / 11 |
| serious Total, serious adverse events | 8 / 15 | 5 / 17 | 4 / 11 |
Outcome results
Primary
Alanine Aminotransferase (ALT)
Screening ALT results, Day 7 ALT results, and change in ALT from screening to Day 7
Time frame: Screening and Day 7
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | Alanine Aminotransferase (ALT) | Day 7 | 27.9 units/L | Standard Deviation 18.8 |
| AB103 0.25 mg/kg | Alanine Aminotransferase (ALT) | Screening | 55.9 units/L | Standard Deviation 99.8 |
| AB103 0.25 mg/kg | Alanine Aminotransferase (ALT) | Change from Screening to Day 7 | -23.2 units/L | Standard Deviation 95.1 |
| AB103 0.5 mg/kg | Alanine Aminotransferase (ALT) | Day 7 | 27.3 units/L | Standard Deviation 26.3 |
| AB103 0.5 mg/kg | Alanine Aminotransferase (ALT) | Screening | 28.1 units/L | Standard Deviation 17.3 |
| AB103 0.5 mg/kg | Alanine Aminotransferase (ALT) | Change from Screening to Day 7 | -0.8 units/L | Standard Deviation 31.2 |
| Placebo | Alanine Aminotransferase (ALT) | Screening | 46.8 units/L | Standard Deviation 57.2 |
| Placebo | Alanine Aminotransferase (ALT) | Change from Screening to Day 7 | -19.8 units/L | Standard Deviation 60.5 |
| Placebo | Alanine Aminotransferase (ALT) | Day 7 | 26.0 units/L | Standard Deviation 13.2 |
Primary
Albumin (Alb)
Screening Alb results, Day 7 Alb results, and change in Alb from screening to Day 7
Time frame: Screening and Day 7
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | Albumin (Alb) | Day 7 | 1.9 g/dL | Standard Deviation 0.9 |
| AB103 0.25 mg/kg | Albumin (Alb) | Screening | 2.5 g/dL | Standard Deviation 0.9 |
| AB103 0.25 mg/kg | Albumin (Alb) | Change from Screening to Day 7 | -0.6 g/dL | Standard Deviation 0.4 |
| AB103 0.5 mg/kg | Albumin (Alb) | Day 7 | 1.7 g/dL | Standard Deviation 0.4 |
| AB103 0.5 mg/kg | Albumin (Alb) | Screening | 2.1 g/dL | Standard Deviation 0.5 |
| AB103 0.5 mg/kg | Albumin (Alb) | Change from Screening to Day 7 | -0.3 g/dL | Standard Deviation 0.2 |
| Placebo | Albumin (Alb) | Screening | 2.3 g/dL | Standard Deviation 0.5 |
| Placebo | Albumin (Alb) | Change from Screening to Day 7 | 0.1 g/dL | Standard Deviation 0.7 |
| Placebo | Albumin (Alb) | Day 7 | 2.3 g/dL | Standard Deviation 0.6 |
Primary
Alkaline Phosphatase (ALP)
Screening ALP results, Day 7 ALP results, and change in ALP from screening to Day 7
Time frame: Screening and Day 7
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | Alkaline Phosphatase (ALP) | Day 7 | 93.1 units/L | Standard Deviation 45.2 |
| AB103 0.25 mg/kg | Alkaline Phosphatase (ALP) | Screening | 97.5 units/L | Standard Deviation 53.5 |
| AB103 0.25 mg/kg | Alkaline Phosphatase (ALP) | Change from Screening to Day 7 | 5.2 units/L | Standard Deviation 40.1 |
| AB103 0.5 mg/kg | Alkaline Phosphatase (ALP) | Day 7 | 84.8 units/L | Standard Deviation 33.9 |
| AB103 0.5 mg/kg | Alkaline Phosphatase (ALP) | Screening | 104.3 units/L | Standard Deviation 47.7 |
| AB103 0.5 mg/kg | Alkaline Phosphatase (ALP) | Change from Screening to Day 7 | -10.6 units/L | Standard Deviation 62.3 |
| Placebo | Alkaline Phosphatase (ALP) | Screening | 108.3 units/L | Standard Deviation 44.2 |
| Placebo | Alkaline Phosphatase (ALP) | Change from Screening to Day 7 | -11.4 units/L | Standard Deviation 34.6 |
| Placebo | Alkaline Phosphatase (ALP) | Day 7 | 100.6 units/L | Standard Deviation 65.9 |
Primary
Apparent Terminal Plasma Half-life (T1/2)
Apparent terminal plasma half-life (T1/2) is the amount of time for plasma concentrations to decline by 50%.
Time frame: Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug.
Population: The pharmacokinetic (PK) analysis population consisted of all intent-to-treat (ITT) patients who received study drug and had a baseline and at least one post-baseline specified plasma sample obtained for quantitative analysis. The number of subjects analyzed reflects the number of subjects for which the parameter could be determined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AB103 0.25 mg/kg | Apparent Terminal Plasma Half-life (T1/2) | 2.61 minutes |
| AB103 0.5 mg/kg | Apparent Terminal Plasma Half-life (T1/2) | 4.89 minutes |
Primary
Apparent Volume of Distribution Under Steady State Conditions (Vss)
Apparent volume of distribution under steady state conditions (Vss) based on drug concentration in plasma
Time frame: Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug.
Population: The pharmacokinetic (PK) analysis population consisted of all intent-to-treat (ITT) patients who received study drug and had a baseline and at least one post-baseline specified plasma sample obtained for quantitative analysis. The number of subjects analyzed reflects the number of subjects for which the parameter could be determined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AB103 0.25 mg/kg | Apparent Volume of Distribution Under Steady State Conditions (Vss) | 100 mL/kg |
| AB103 0.5 mg/kg | Apparent Volume of Distribution Under Steady State Conditions (Vss) | 135 mL/kg |
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC)
Area under the plasma concentration versus time curve (AUC) from time zero to infinity following a single dose of study drug, obtained by noncompartmental methods. It is an integrated measure of study drug plasma exposure.
Time frame: Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug.
Population: The pharmacokinetic (PK) analysis population consisted of all intent-to-treat (ITT) patients who received study drug and had a baseline and at least one post-baseline specified plasma sample obtained for quantitative analysis. The number of subjects analyzed reflects the number of subjects for which the parameter could be determined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AB103 0.25 mg/kg | Area Under the Plasma Concentration Versus Time Curve (AUC) | 8497 ng*min/mL |
| AB103 0.5 mg/kg | Area Under the Plasma Concentration Versus Time Curve (AUC) | 16921 ng*min/mL |
Primary
Aspartate Aminotransferase (AST)
Screening AST results, Day 7 AST results, and change in AST from screening to Day 7
Time frame: Screening and Day 7
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | Aspartate Aminotransferase (AST) | Screening | 35.8 units/L | Standard Deviation 30.6 |
| AB103 0.25 mg/kg | Aspartate Aminotransferase (AST) | Change from Screening to Day 7 | -1.2 units/L | Standard Deviation 30.7 |
| AB103 0.25 mg/kg | Aspartate Aminotransferase (AST) | Day 7 | 30.6 units/L | Standard Deviation 17.1 |
| AB103 0.5 mg/kg | Aspartate Aminotransferase (AST) | Screening | 37.4 units/L | Standard Deviation 28.3 |
| AB103 0.5 mg/kg | Aspartate Aminotransferase (AST) | Day 7 | 24.3 units/L | Standard Deviation 10.1 |
| AB103 0.5 mg/kg | Aspartate Aminotransferase (AST) | Change from Screening to Day 7 | -9.3 units/L | Standard Deviation 21.7 |
| Placebo | Aspartate Aminotransferase (AST) | Screening | 32.0 units/L | Standard Deviation 19.2 |
| Placebo | Aspartate Aminotransferase (AST) | Change from Screening to Day 7 | 0.1 units/L | Standard Deviation 9.6 |
| Placebo | Aspartate Aminotransferase (AST) | Day 7 | 27.4 units/L | Standard Deviation 9.7 |
Primary
Categorical Change in QTcF
Number and percentage of patients with a change in QTcF of \> 30 msec; number and percentage of patients with a change in QTcF of \> 60 msec
Time frame: Pre-dose and up to 24 hours post-dose
Population: Safety population: all randomized patients who received study drug. The number of patients analyzed is the number of patients with non-missing data as noted in results.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AB103 0.25 mg/kg | Categorical Change in QTcF | Patients with a change in QTcF of > 30 msec | 1 Participants |
| AB103 0.25 mg/kg | Categorical Change in QTcF | Patients with a change in QTcF of > 60 msec | 1 Participants |
| AB103 0.5 mg/kg | Categorical Change in QTcF | Patients with a change in QTcF of > 30 msec | 3 Participants |
| AB103 0.5 mg/kg | Categorical Change in QTcF | Patients with a change in QTcF of > 60 msec | 2 Participants |
| Placebo | Categorical Change in QTcF | Patients with a change in QTcF of > 30 msec | 2 Participants |
| Placebo | Categorical Change in QTcF | Patients with a change in QTcF of > 60 msec | 1 Participants |
Primary
Clearance (CL)
Clearance (CL) is the volume of plasma completely cleared of drug per unit of time.
Time frame: Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug.
Population: The pharmacokinetic (PK) analysis population consisted of all intent-to-treat (ITT) patients who received study drug and had a baseline and at least one post-baseline specified plasma sample obtained for quantitative analysis. The number of subjects analyzed reflects the number of subjects for which the parameter could be determined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AB103 0.25 mg/kg | Clearance (CL) | 29.42 mL/min/kg |
| AB103 0.5 mg/kg | Clearance (CL) | 29.55 mL/min/kg |
Primary
Hemoglobin (Hgb)
Screening Hgb results, Day 7 Hgb results, and change in Hgb from screening to Day 7
Time frame: Screening and Day 7
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | Hemoglobin (Hgb) | Day 7 | 8.8 g/dL | Standard Deviation 2.1 |
| AB103 0.25 mg/kg | Hemoglobin (Hgb) | Screening | 11.5 g/dL | Standard Deviation 2.2 |
| AB103 0.25 mg/kg | Hemoglobin (Hgb) | Change from Screening to Day 7 | -2.9 g/dL | Standard Deviation 2.1 |
| AB103 0.5 mg/kg | Hemoglobin (Hgb) | Day 7 | 8.9 g/dL | Standard Deviation 1.1 |
| AB103 0.5 mg/kg | Hemoglobin (Hgb) | Screening | 11.0 g/dL | Standard Deviation 1.5 |
| AB103 0.5 mg/kg | Hemoglobin (Hgb) | Change from Screening to Day 7 | -2.5 g/dL | Standard Deviation 1.5 |
| Placebo | Hemoglobin (Hgb) | Screening | 10.5 g/dL | Standard Deviation 2.6 |
| Placebo | Hemoglobin (Hgb) | Change from Screening to Day 7 | -1.3 g/dL | Standard Deviation 2.4 |
| Placebo | Hemoglobin (Hgb) | Day 7 | 9.0 g/dL | Standard Deviation 1.4 |
Primary
International Normalized Ratio (INR)
Screening INR results, Day 7 INR results, and change in INR from screening to Day 7. In general, the higher the INR value, the longer it takes for blood to form a clot.
Time frame: Screening and Day 7
Population: The safety analysis population consisted of all randomized patients who received study drug. One of the 0.25 mg/kg patients did not have a Screening INR result. Participant numbers in some rows differ from the overall number analyzed due to missing data as conveyed in the number of participants in each treatment group within a row.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | International Normalized Ratio (INR) | Change from Screening to Day 7 | -0.1 unitless | Standard Deviation 0.2 |
| AB103 0.25 mg/kg | International Normalized Ratio (INR) | Screening | 1.29 unitless | Standard Deviation 0.22 |
| AB103 0.25 mg/kg | International Normalized Ratio (INR) | Day 7 | 1.2 unitless | Standard Deviation 0.1 |
| AB103 0.5 mg/kg | International Normalized Ratio (INR) | Day 7 | 1.2 unitless | Standard Deviation 0.1 |
| AB103 0.5 mg/kg | International Normalized Ratio (INR) | Screening | 1.43 unitless | Standard Deviation 0.33 |
| AB103 0.5 mg/kg | International Normalized Ratio (INR) | Change from Screening to Day 7 | -0.2 unitless | Standard Deviation 0.3 |
| Placebo | International Normalized Ratio (INR) | Screening | 1.41 unitless | Standard Deviation 0.38 |
| Placebo | International Normalized Ratio (INR) | Change from Screening to Day 7 | -0.2 unitless | Standard Deviation 0.3 |
| Placebo | International Normalized Ratio (INR) | Day 7 | 1.3 unitless | Standard Deviation 0.3 |
Primary
Maximum Plasma Concentration (Cmax)
Maximum plasma concentration (observed)
Time frame: Prior to infusion, at mid infusion time, end of infusion, and at 2, 5, 10, 20, 30, 60 min and 120 minutes after completion of the IV infusion of study drug.
Population: The pharmacokinetic (PK) analysis population consisted of all intent-to-treat (ITT) patients who received study drug and had a baseline and at least one post-baseline specified plasma sample obtained for quantitative analysis. The number of subjects analyzed reflects the number of subjects for which the parameter could be determined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AB103 0.25 mg/kg | Maximum Plasma Concentration (Cmax) | 899 ng/mL |
| AB103 0.5 mg/kg | Maximum Plasma Concentration (Cmax) | 1484 ng/mL |
Primary
Number of Subjects With One or More Adverse Events (AEs) During the Treatment Period
An AE is any untoward medical occurrence in a subject administered study drug and that does not necessarily have a causal relationship with the study drug. An AE could therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug.
Time frame: 7 days
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AB103 0.25 mg/kg | Number of Subjects With One or More Adverse Events (AEs) During the Treatment Period | 14 Participants |
| AB103 0.5 mg/kg | Number of Subjects With One or More Adverse Events (AEs) During the Treatment Period | 16 Participants |
| Placebo | Number of Subjects With One or More Adverse Events (AEs) During the Treatment Period | 9 Participants |
Primary
Number of Subjects With One or More Serious Adverse Events (SAEs)
A serious adverse event (SAE) is an AE occurring during any study phase and at any dose of the study drug (AB103 or placebo) that fulfills one or more of the following criteria: * Results in death * Is life-threatening (i.e., the subject was, in the opinion of the Investigator, at immediate risk of death from the event as it occurred) * Requires or prolongs hospitalization * Results in persistent or significant disability or incapacity (i.e., the event causes a substantial disruption of a person's ability to conduct normal life functions) * Is a congenital anomaly or birth defect, or * Is an important and significant medical event.
Time frame: 28 days
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AB103 0.25 mg/kg | Number of Subjects With One or More Serious Adverse Events (SAEs) | 8 Participants |
| AB103 0.5 mg/kg | Number of Subjects With One or More Serious Adverse Events (SAEs) | 5 Participants |
| Placebo | Number of Subjects With One or More Serious Adverse Events (SAEs) | 4 Participants |
Primary
Platelet (PLT) Count
Screening PLT results, Day 7 PLT results, and change in PLT from screening to Day 7
Time frame: Screening and Day 7
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | Platelet (PLT) Count | Day 7 | 401.5 thousand cells per microliter | Standard Deviation 168.8 |
| AB103 0.25 mg/kg | Platelet (PLT) Count | Screening | 300.2 thousand cells per microliter | Standard Deviation 182.2 |
| AB103 0.25 mg/kg | Platelet (PLT) Count | Change from Screening to Day 7 | 81.8 thousand cells per microliter | Standard Deviation 237.1 |
| AB103 0.5 mg/kg | Platelet (PLT) Count | Day 7 | 341.8 thousand cells per microliter | Standard Deviation 140.6 |
| AB103 0.5 mg/kg | Platelet (PLT) Count | Screening | 215.1 thousand cells per microliter | Standard Deviation 82 |
| AB103 0.5 mg/kg | Platelet (PLT) Count | Change from Screening to Day 7 | 125.1 thousand cells per microliter | Standard Deviation 144.6 |
| Placebo | Platelet (PLT) Count | Screening | 255.3 thousand cells per microliter | Standard Deviation 130 |
| Placebo | Platelet (PLT) Count | Change from Screening to Day 7 | 49.9 thousand cells per microliter | Standard Deviation 160.2 |
| Placebo | Platelet (PLT) Count | Day 7 | 318.3 thousand cells per microliter | Standard Deviation 148.2 |
Primary
QT Interval With Fridericia's Correction (QTcF)
Pre-dose QTcF, post-dose QTcF, change in QTcF from pre-dose to post-dose
Time frame: Pre-dose and up to 24 hours post-dose
Population: Safety population: all randomized patients who received study drug. The number of patients analyzed is the number of patients with non-missing data as noted in results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | QT Interval With Fridericia's Correction (QTcF) | Post-dose QTcF | 409.2 msec | Standard Deviation 23.1 |
| AB103 0.25 mg/kg | QT Interval With Fridericia's Correction (QTcF) | Pre-dose QTcF | 419.1 msec | Standard Deviation 39.3 |
| AB103 0.25 mg/kg | QT Interval With Fridericia's Correction (QTcF) | Change in QTcF from pre-dose to post-dose | -9.9 msec | Standard Deviation 37.2 |
| AB103 0.5 mg/kg | QT Interval With Fridericia's Correction (QTcF) | Post-dose QTcF | 403.1 msec | Standard Deviation 39.3 |
| AB103 0.5 mg/kg | QT Interval With Fridericia's Correction (QTcF) | Pre-dose QTcF | 401.8 msec | Standard Deviation 16.8 |
| AB103 0.5 mg/kg | QT Interval With Fridericia's Correction (QTcF) | Change in QTcF from pre-dose to post-dose | 1.3 msec | Standard Deviation 36.1 |
| Placebo | QT Interval With Fridericia's Correction (QTcF) | Pre-dose QTcF | 405.1 msec | Standard Deviation 38.6 |
| Placebo | QT Interval With Fridericia's Correction (QTcF) | Change in QTcF from pre-dose to post-dose | 8.9 msec | Standard Deviation 31 |
| Placebo | QT Interval With Fridericia's Correction (QTcF) | Post-dose QTcF | 407.4 msec | Standard Deviation 29.6 |
Primary
Serum Creatinine (sCr)
Screening sCr results, Day 7 sCr results, and change in sCr from screening to Day 7
Time frame: Screening and Day 7
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | Serum Creatinine (sCr) | Day 7 | 1.1 mg/dL | Standard Deviation 0.9 |
| AB103 0.25 mg/kg | Serum Creatinine (sCr) | Screening | 1.2 mg/dL | Standard Deviation 0.5 |
| AB103 0.25 mg/kg | Serum Creatinine (sCr) | Change from Screening to Day 7 | -0.1 mg/dL | Standard Deviation 0.7 |
| AB103 0.5 mg/kg | Serum Creatinine (sCr) | Day 7 | 1.3 mg/dL | Standard Deviation 1.7 |
| AB103 0.5 mg/kg | Serum Creatinine (sCr) | Screening | 1.2 mg/dL | Standard Deviation 1 |
| AB103 0.5 mg/kg | Serum Creatinine (sCr) | Change from Screening to Day 7 | 0.1 mg/dL | Standard Deviation 2 |
| Placebo | Serum Creatinine (sCr) | Screening | 1.2 mg/dL | Standard Deviation 0.7 |
| Placebo | Serum Creatinine (sCr) | Change from Screening to Day 7 | -0.2 mg/dL | Standard Deviation 0.6 |
| Placebo | Serum Creatinine (sCr) | Day 7 | 1.0 mg/dL | Standard Deviation 0.4 |
Primary
Total Bilirubin (Tbili)
Screening Tbili results, Day 7 Tbili results, and change in Tbili from screening to Day 7
Time frame: Screening and Day 7
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | Total Bilirubin (Tbili) | Day 7 | 0.6 mg/dL | Standard Deviation 0.2 |
| AB103 0.25 mg/kg | Total Bilirubin (Tbili) | Screening | 1.2 mg/dL | Standard Deviation 0.7 |
| AB103 0.25 mg/kg | Total Bilirubin (Tbili) | Change from Screening to Day 7 | -0.8 mg/dL | Standard Deviation 0.6 |
| AB103 0.5 mg/kg | Total Bilirubin (Tbili) | Day 7 | 0.6 mg/dL | Standard Deviation 0.3 |
| AB103 0.5 mg/kg | Total Bilirubin (Tbili) | Screening | 1.2 mg/dL | Standard Deviation 0.8 |
| AB103 0.5 mg/kg | Total Bilirubin (Tbili) | Change from Screening to Day 7 | -0.5 mg/dL | Standard Deviation 0.5 |
| Placebo | Total Bilirubin (Tbili) | Screening | 1.5 mg/dL | Standard Deviation 1.7 |
| Placebo | Total Bilirubin (Tbili) | Change from Screening to Day 7 | -0.4 mg/dL | Standard Deviation 1.4 |
| Placebo | Total Bilirubin (Tbili) | Day 7 | 1.1 mg/dL | Standard Deviation 0.8 |
Primary
Total White Blood Cell (WBC) Count
Screening WBC results, Day 7 WBC results, and change in WBC from screening to Day 7
Time frame: Screening and Day 7
Population: The safety analysis population consisted of all randomized patients who received study drug (N=43). The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | Total White Blood Cell (WBC) Count | Day 7 | 14.3 thousand cells per microliter | Standard Deviation 6.7 |
| AB103 0.25 mg/kg | Total White Blood Cell (WBC) Count | Screening | 17.8 thousand cells per microliter | Standard Deviation 10 |
| AB103 0.25 mg/kg | Total White Blood Cell (WBC) Count | Change from Screening to Day 7 | -5.0 thousand cells per microliter | Standard Deviation 9.3 |
| AB103 0.5 mg/kg | Total White Blood Cell (WBC) Count | Day 7 | 12.5 thousand cells per microliter | Standard Deviation 5.1 |
| AB103 0.5 mg/kg | Total White Blood Cell (WBC) Count | Screening | 14.7 thousand cells per microliter | Standard Deviation 8.8 |
| AB103 0.5 mg/kg | Total White Blood Cell (WBC) Count | Change from Screening to Day 7 | -3.0 thousand cells per microliter | Standard Deviation 10.9 |
| Placebo | Total White Blood Cell (WBC) Count | Screening | 21.7 thousand cells per microliter | Standard Deviation 16.2 |
| Placebo | Total White Blood Cell (WBC) Count | Change from Screening to Day 7 | -11.2 thousand cells per microliter | Standard Deviation 14.9 |
| Placebo | Total White Blood Cell (WBC) Count | Day 7 | 12.3 thousand cells per microliter | Standard Deviation 2.4 |
Secondary
C-reactive Protein (CRP)
Screening CRP results, Day 7 CRP results, and change in CRP from screening to Day 7
Time frame: Screening and Day 7
Population: The population is all randomized patients who received study drug. The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AB103 0.25 mg/kg | C-reactive Protein (CRP) | Screening | 29.2 mg/dL | Standard Deviation 12.3 |
| AB103 0.25 mg/kg | C-reactive Protein (CRP) | Day 7 | 11.7 mg/dL | Standard Deviation 10 |
| AB103 0.25 mg/kg | C-reactive Protein (CRP) | Change from Screening to Day 7 | -19.2 mg/dL | Standard Deviation 14.6 |
| AB103 0.5 mg/kg | C-reactive Protein (CRP) | Day 7 | 7.5 mg/dL | Standard Deviation 4.4 |
| AB103 0.5 mg/kg | C-reactive Protein (CRP) | Change from Screening to Day 7 | -22.7 mg/dL | Standard Deviation 5.9 |
| AB103 0.5 mg/kg | C-reactive Protein (CRP) | Screening | 27.5 mg/dL | Standard Deviation 6.2 |
| Placebo | C-reactive Protein (CRP) | Change from Screening to Day 7 | -20.5 mg/dL | Standard Deviation 11 |
| Placebo | C-reactive Protein (CRP) | Day 7 | 4.0 mg/dL | Standard Deviation 3 |
| Placebo | C-reactive Protein (CRP) | Screening | 20.6 mg/dL | Standard Deviation 13.2 |
Secondary
Day 14 Sequential Organ Failure Assessment (SOFA) Score
Day 14 SOFA score is the sum of individual SOFA score components at Day 14. Results include last observation carried forward (LOCF) imputation for missing values. SOFA total scores range from 0 to 24, with higher scores reflecting a worse clinical status or outcome. A SOFA total score of 0 or 1 reflects resolution of organ dysfunction/failure.
Time frame: 14 days
Population: Modified intent-to-treat (mITT) population: all randomized patients who received the proper study drug (AB103 or Placebo), had a definitive surgical diagnosis of NSTI, were not mis-dosed, and did not have a CD4 count \<200 cells/mm3. Proper study drug administration meant that study drug administration did not deviate from the planned administration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AB103 0.25 mg/kg | Day 14 Sequential Organ Failure Assessment (SOFA) Score | 1.07 score on a scale | Standard Deviation 1 |
| AB103 0.5 mg/kg | Day 14 Sequential Organ Failure Assessment (SOFA) Score | 0.71 score on a scale | Standard Deviation 0.83 |
| Placebo | Day 14 Sequential Organ Failure Assessment (SOFA) Score | 2.70 score on a scale | Standard Deviation 2.79 |
p-value: 0.016ANOVA
Secondary
Day 14 Sequential Organ Failure Assessment (SOFA) Score Less Than or Equal to 1
Number and percentage of patients with Day 14 Sequential Organ Failure Assessment (SOFA) score less than or equal to 1. SOFA total scores range from 0 to 24, with higher scores reflecting a worse clinical status or outcome. A SOFA total score of 0 or 1 reflects resolution of organ dysfunction/failure.
Time frame: 14 days
Population: Modified intent-to-treat (mITT) population: all randomized patients who received the proper study drug (AB103 or Placebo), had a definitive surgical diagnosis of NSTI, were not mis-dosed, and did not have a CD4 count \<200 cells/mm3. Proper study drug administration meant that study drug administration did not deviate from the planned administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AB103 0.25 mg/kg | Day 14 Sequential Organ Failure Assessment (SOFA) Score Less Than or Equal to 1 | 10 Participants |
| AB103 0.5 mg/kg | Day 14 Sequential Organ Failure Assessment (SOFA) Score Less Than or Equal to 1 | 13 Participants |
| Placebo | Day 14 Sequential Organ Failure Assessment (SOFA) Score Less Than or Equal to 1 | 4 Participants |
Comparison: The null hypothesis was that the frequency of Day 14 SOFA score less than or equal to 1 was not different among treatment groups.p-value: 0.019Chi-squared
Secondary
Hospital Length of Stay (LOS)
The duration of hospital stay over the 28-day study period.
Time frame: 28 days
Population: Modified intent-to-treat (mITT) population: all randomized patients who received the proper study drug (AB103 or Placebo), had a definitive surgical diagnosis of NSTI, were not mis-dosed, and did not have a CD4 count \<200 cells/mm3. Proper study drug administration meant that study drug administration did not deviate from the planned administration. The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AB103 0.25 mg/kg | Hospital Length of Stay (LOS) | 17.1 days | Standard Deviation 7.96 |
| AB103 0.5 mg/kg | Hospital Length of Stay (LOS) | 17.4 days | Standard Deviation 9.07 |
| Placebo | Hospital Length of Stay (LOS) | 20.0 days | Standard Deviation 6.93 |
p-value: 0.11Wilcoxon (Mann-Whitney)
Secondary
Intensive Care Unit-free Days (ICU-free Days)
The number of intensive care unit-free days (ICU-free days)
Time frame: 28 days
Population: Modified intent-to-treat (mITT) population: all randomized patients who received the proper study drug (AB103 or Placebo), had a definitive surgical diagnosis of NSTI, were not mis-dosed, and did not have a CD4 count \<200 cells/mm3. Proper study drug administration meant that study drug administration did not deviate from the planned administration. The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AB103 0.25 mg/kg | Intensive Care Unit-free Days (ICU-free Days) | 21.7 ICU-free days | Standard Deviation 8.48 |
| AB103 0.5 mg/kg | Intensive Care Unit-free Days (ICU-free Days) | 21.3 ICU-free days | Standard Deviation 6.21 |
| Placebo | Intensive Care Unit-free Days (ICU-free Days) | 17.1 ICU-free days | Standard Deviation 9.88 |
p-value: 0.18Wilcoxon (Mann-Whitney)
Secondary
Ventilator-free Days
The number of ventilator-free days (days without ventilator use)
Time frame: 28 days
Population: Modified intent-to-treat (mITT) population: all randomized patients who received the proper study drug (AB103 or Placebo), had a definitive surgical diagnosis of NSTI, were not mis-dosed, and did not have a CD4 count \<200 cells/mm3. Proper study drug administration meant that study drug administration did not deviate from the planned administration. The number of patients analyzed is the number of patients with non-missing data in this population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AB103 0.25 mg/kg | Ventilator-free Days | 23.5 ventilator-free days | Standard Deviation 8.75 |
| AB103 0.5 mg/kg | Ventilator-free Days | 24.1 ventilator-free days | Standard Deviation 6.25 |
| Placebo | Ventilator-free Days | 20.8 ventilator-free days | Standard Deviation 9.14 |
p-value: 0.19Wilcoxon (Mann-Whitney)