AB103 Peptide Antagonist in Healthy Volunteers

Study Overview
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Brief Summary
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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
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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: If none of the 5 AB103 subjects in a cohort experienced a non-extreme DLT, escalation to the next dose cohort was to occur. 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). 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. 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.

Official Title
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Phase 1, Double Blind, Placebo-Controlled, Dose Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Clinical Trial of AB103, A Peptide Antagonist in Healthy Volunteers

Conditions
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Healthy Volunteer Safety Study

Intervention / Treatment
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* Drug: AB103
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AB103 7.5 µg/kg<br>AB103 7.5 µg/kg administered as a single IV infusion | Drug: AB103<br>* 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<br>|
| Experimental: AB103 37.5 µg/kg<br>AB103 37.5 µg/kg administered as a single IV infusion | Drug: AB103<br>* 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<br>|
| Experimental: AB103 150 µg/kg<br>AB103 150 µg/kg administered as a single IV infusion | Drug: AB103<br>* 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<br>|
| Experimental: AB103 450 µg/kg<br>AB103 450 µg/kg administered as a single IV infusion | Drug: AB103<br>* 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<br>|
| Placebo Comparator: Placebo<br>Normal saline (0.9% sodium chloride) administered as a single IV infusion | Drug: Placebo<br>* Single intravenous infusion of normal saline (0.9% sodium chloride) administered over approximately 10 minutes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2 weeks | 
| 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. | 2 weeks | 
| 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. | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| Cmax | Maximum plasma concentration | 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) | Apparent terminal plasma half-life (T1/2) is the amount of time for plasma concentrations to decline by 50%. | 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) | Clearance (CL) is the volume of plasma completely cleared of drug per unit of time. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, septic shock