Healthy Volunteer Safety Study
Conditions
Keywords
sepsis, septic shock
Brief summary
The primary objective of this study is to establish the safety profile and maximum tolerated dose (MTD) of AB103 given as a single intravenous (IV) infusion in healthy volunteers.
Detailed description
After consent and establishing eligibility for the study, each subject received a single IV infusion of escalating doses of AB103 (7.5, 37.5, 150, 450 μg/kg in 5 subjects at each dose) or placebo (n=5). Screening blood chemistry, hematology, coagulation, urinalysis, vital signs, and electrocardiogram (ECG) were used to assure medical fitness to participate in the study. These measures were repeated during and after treatment with AB103 to monitor for adverse events (AEs). ECG and pulse oximetry was monitored continuously starting 15 minutes before the infusion and for 2 hours after each infusion. Vital signs (sitting blood pressure, temperature, heart rate, respiratory rate, and pulse oximetry) and ECG measurements were recorded every 15 minutes for the first two hours starting from the beginning of the infusion and then approximately 24 hours later. Blood chemistry, hematology, coagulation, and urinalysis, were repeated one day and one week after infusions. AEs either observed by the investigator or reported spontaneously by the subjects were recorded at each study visit. Subjects kept a 7-day diary starting on the day of infusion to record any AEs. The primary basis on which escalation was based was dose limiting toxicities (DLTs) defined as the emergence of one or more selected AEs that reached a threshold which justified stopping the trial. After safety monitoring committee review of safety data, progression to the next cohort was to occur as follows: 1. If none of the 5 AB103 subjects in a cohort experienced a non-extreme DLT, escalation to the next dose cohort was to occur. 2. If 1 of 5 subjects receiving AB103 in a cohort experienced a non-extreme DLT, then a total of 8 subjects (6 active: 2 placebo) were to be enrolled in that cohort before escalating to the next dose (escalation will only occur if no additional subjects (2 total) have a non-extreme DLT). 3. If there were 0/6 or 1/6 active subjects with a non-extreme DLT at the highest dose, the highest dose was to be considered the MTD. If there were 2/6 active subjects with a non-extreme DLT in a cohort, then the next lowest dose was to be considered the MTD. 4. If an extreme DLT occurred, the study was to be halted immediately. Subjects in Cohorts #1 to #3 had a blood sample (40 milliliters, mL) drawn pre-infusion, 24 hours after the infusion (Day 2), and a final sample at the Day 6-8 clinic visit (total of 120 mL) for leukocyte phenotyping by flow cytometry. Subjects in Cohort #4 had a blood sample (40 mL) drawn pre-infusion, 1 hour after the infusion, and a final sample at the Day 6-8 clinic visit (total of 120 mL) for leukocyte phenotyping by flow cytometry. For the pharmacokinetic (PK) analysis, blood was collected at the mid-point of the infusion and 1, 2, 5, 10, 20, 30, and 60 minutes and approximately 24 hours post-infusion, and plasma was isolated for quantitation of AB103 peptide concentrations.
Interventions
DRUGAB103
Single intravenous infusion at doses of 7.5 µg/kg, 37.5 µg/kg, 150 µg/kg, or 450 µg/kg administered over approximately 10 minutes
DRUGPlacebo
Single intravenous infusion of normal saline (0.9% sodium chloride) administered over approximately 10 minutes
Sponsors
Atox Bio Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Be able to read, understand and sign the Informed Consent form and be willing to participate in all study procedures for the duration of the study. * Be 18-to-40 years-of-age. * Have adequate venous access. * Have a body mass index between 20 and 29 kg/m2. * Have a history and physical examination that demonstrate no clinically significant contraindication for participating in the study, in the judgment of the admitting physician and/or the site investigator. * Have vital signs as follows: resting heart rate between 50 and 90 beats per minute (bpm), systolic blood pressure (BP) below 150 mm Hg and diastolic BP below 90 mm Hg. * Have all blood chemistry, hematology, coagulation, and urinalysis analyte levels within 10% of normal laboratory limits. * If female, not be pregnant or breast-feeding, nor plan to become pregnant for the duration of the study, have a negative pregnancy test. * Agree to exercise adequate birth control from the time of the screening procedures to 14 days after the investigational agent administration (both males and females). * Have an electrocardiogram (ECG) performed that demonstrates normal sinus rhythm, normal conductivity, and no clinically significant arrhythmias.
Exclusion criteria
* Be pregnant or lactating. * Have autoimmune disease or asthma. * Have been febrile within 3-days of the first infusion. * Have a history of migraine headaches, as diagnosed by a physician. * Have any acute or chronic medical illnesses or other condition that, in the opinion of the Investigator, might jeopardize the safety of the patient, or the adequate evaluation of study results. * Be taking any medications to treat a chronic medical condition. * Have participated in a research study where they received any experimental products within 30 days prior to study entry. * Have ongoing drug abuse/dependence (including alcohol) by medical history. * Have taken, within 14 days of planned dosing, any prescription or non-prescription medication (including ibuprofen, aspirin, of non-steroidal anti-inflammatory drugs) unless the Principal Investigator/Sub-Investigator, in consultation with the Medical Monitor, provides a statement justifying that the medication taken will not impact the results of this study (with rare exceptions taking prescription drugs will be grounds for exclusion). * Have donated a unit of blood within the preceding 4-week period. * Have allergy to either sulfa- or penicillin-based drugs. * Have a history of vagal responses resulting in bradycardia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number Adverse Events (AEs) | 2 weeks | 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 Serious Adverse Events (SAEs) | 2 weeks | 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. |
| Number of Dose-limiting Toxicities (DLTs) | 2 weeks | DLTs were defined as the emergence of one or more selected AEs that reached a threshold that may justify stopping the trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve (AUC) | Whole blood was collected pre-dose; at the mid-point of the infusion; at 1, 2, 5, 10, 20, 30, and 60 minutes post-infusion; and at approximately 24 hours post-infusion for the measurement of AB103 plasma concentrations. | Area under the plasma concentration-time curve (AUC) from time zero to infinity following a single dose of study drug, obtained via noncompartmental methods. It is an integrated measure of study drug plasma exposure. |
| Clearance (CL) | Whole blood was collected pre-dose; at the mid-point of the infusion; at 1, 2, 5, 10, 20, 30, and 60 minutes post-infusion; and at approximately 24 hours post-infusion for the measurement of AB103 plasma concentrations. | Clearance (CL) is the volume of plasma completely cleared of drug per unit of time. |
| Cmax | Whole blood was collected pre-dose; at the mid-point of the infusion; at 1, 2, 5, 10, 20, 30, and 60 minutes post-infusion; and at approximately 24 hours post-infusion for the measurement of AB103 plasma concentrations. | Maximum plasma concentration |
| Apparent Terminal Plasma Half-life (T1/2) | Whole blood was collected pre-dose; at the mid-point of the infusion; at 1, 2, 5, 10, 20, 30, and 60 minutes post-infusion; and at approximately 24 hours post-infusion for the measurement of AB103 plasma concentrations. | Apparent terminal plasma half-life (T1/2) is the amount of time for plasma concentrations to decline by 50%. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited at the University of Maryland School of Medicine starting 7 September 2010. The study concluded 10 April 2011.
Pre-assignment details
One consented and screened subject found to be eligible was not randomized into the study because the target number of subjects had already been achieved.
Participants by arm
| Arm | Count |
|---|---|
| AB103 7.5 µg/kg AB103 7.5 µg/kg administered as a single IV infusion | 5 |
| AB103 37.5 µg/kg AB103 37.5 µg/kg administered as a single IV infusion | 5 |
| AB103 150 µg/kg AB103 150 µg/kg administered as a single IV infusion | 5 |
| AB103 450 µg/kg AB103 450 µg/kg administered as a single IV infusion | 5 |
| Placebo Normal saline (0.9% sodium chloride) administered as a single IV infusion | 5 |
| Total | 25 |
Baseline characteristics
| Characteristic | AB103 37.5 µg/kg | AB103 150 µg/kg | AB103 450 µg/kg | AB103 7.5 µg/kg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 25 Participants |
| Age, Continuous | 29 years STANDARD_DEVIATION 6 | 34 years STANDARD_DEVIATION 5 | 30 years STANDARD_DEVIATION 4 | 28 years STANDARD_DEVIATION 7 | 30 years STANDARD_DEVIATION 8 | 30 years STANDARD_DEVIATION 6 |
| Region of Enrollment United States | 5 participants | 5 participants | 5 participants | 5 participants | 5 participants | 25 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 2 Participants | 3 Participants | 4 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 1 / 5 | 1 / 5 | 1 / 5 | 2 / 5 | 2 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 |
Outcome results
Primary
Number Adverse Events (AEs)
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: 2 weeks
Population: The analysis population consisted of all subjects who received a dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AB103 7.5 µg/kg | Number Adverse Events (AEs) | 7 adverse events |
| AB103 37.5 µg/kg | Number Adverse Events (AEs) | 2 adverse events |
| AB103 150 µg/kg | Number Adverse Events (AEs) | 1 adverse events |
| AB103 450 µg/kg | Number Adverse Events (AEs) | 9 adverse events |
| Placebo | Number Adverse Events (AEs) | 3 adverse events |
Primary
Number of Dose-limiting Toxicities (DLTs)
DLTs were defined as the emergence of one or more selected AEs that reached a threshold that may justify stopping the trial.
Time frame: 2 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AB103 7.5 µg/kg | Number of Dose-limiting Toxicities (DLTs) | 0 DLTs |
| AB103 37.5 µg/kg | Number of Dose-limiting Toxicities (DLTs) | 0 DLTs |
| AB103 150 µg/kg | Number of Dose-limiting Toxicities (DLTs) | 0 DLTs |
| AB103 450 µg/kg | Number of Dose-limiting Toxicities (DLTs) | 0 DLTs |
| Placebo | Number of Dose-limiting Toxicities (DLTs) | 0 DLTs |
Primary
Number of 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: 2 weeks
Population: The analysis population consisted of all subjects receiving a dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AB103 7.5 µg/kg | Number of Serious Adverse Events (SAEs) | 0 serious adverse events |
| AB103 37.5 µg/kg | Number of Serious Adverse Events (SAEs) | 0 serious adverse events |
| AB103 150 µg/kg | Number of Serious Adverse Events (SAEs) | 0 serious adverse events |
| AB103 450 µg/kg | Number of Serious Adverse Events (SAEs) | 0 serious adverse events |
| Placebo | Number of Serious Adverse Events (SAEs) | 0 serious adverse events |
Secondary
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: Whole blood was collected pre-dose; at the mid-point of the infusion; at 1, 2, 5, 10, 20, 30, and 60 minutes post-infusion; and at approximately 24 hours post-infusion for the measurement of AB103 plasma concentrations.
Population: This outcome measure could not be determined in the 7.5 µg/kg dose group because of the frequency of undetectable plasma concentrations. It was not determined for placebo subjects (undetectable plasma concentrations).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AB103 7.5 µg/kg | Apparent Terminal Plasma Half-life (T1/2) | 1.42 hours (h) |
| AB103 37.5 µg/kg | Apparent Terminal Plasma Half-life (T1/2) | 1.36 hours (h) |
| AB103 150 µg/kg | Apparent Terminal Plasma Half-life (T1/2) | 1.28 hours (h) |
Secondary
Area Under the Plasma Concentration-time Curve (AUC)
Area under the plasma concentration-time curve (AUC) from time zero to infinity following a single dose of study drug, obtained via noncompartmental methods. It is an integrated measure of study drug plasma exposure.
Time frame: Whole blood was collected pre-dose; at the mid-point of the infusion; at 1, 2, 5, 10, 20, 30, and 60 minutes post-infusion; and at approximately 24 hours post-infusion for the measurement of AB103 plasma concentrations.
Population: AUC could not be determined in the AB103 7.5 µg/kg group and the placebo group because of the number of plasma concentration results that were undetectable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AB103 7.5 µg/kg | Area Under the Plasma Concentration-time Curve (AUC) | 527 ng*min/mL |
| AB103 37.5 µg/kg | Area Under the Plasma Concentration-time Curve (AUC) | 2085 ng*min/mL |
| AB103 150 µg/kg | Area Under the Plasma Concentration-time Curve (AUC) | 5831 ng*min/mL |
Secondary
Clearance (CL)
Clearance (CL) is the volume of plasma completely cleared of drug per unit of time.
Time frame: Whole blood was collected pre-dose; at the mid-point of the infusion; at 1, 2, 5, 10, 20, 30, and 60 minutes post-infusion; and at approximately 24 hours post-infusion for the measurement of AB103 plasma concentrations.
Population: Clearance was not determined in the 7.5 µg/kg dose group because of the frequency of undetectable AB103 plasma concentrations. Clearance was not determined in the placebo group (undetectable plasma concentrations).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AB103 7.5 µg/kg | Clearance (CL) | 71 mL/min/kg |
| AB103 37.5 µg/kg | Clearance (CL) | 72 mL/min/kg |
| AB103 150 µg/kg | Clearance (CL) | 77 mL/min/kg |
Secondary
Cmax
Maximum plasma concentration
Time frame: Whole blood was collected pre-dose; at the mid-point of the infusion; at 1, 2, 5, 10, 20, 30, and 60 minutes post-infusion; and at approximately 24 hours post-infusion for the measurement of AB103 plasma concentrations.
Population: Cmax is not available (applicable) to placebo patients (no detectable plasma concentrations).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AB103 7.5 µg/kg | Cmax | 10.63 ng/mL |
| AB103 37.5 µg/kg | Cmax | 52.67 ng/mL |
| AB103 150 µg/kg | Cmax | 190.90 ng/mL |
| AB103 450 µg/kg | Cmax | 611.19 ng/mL |