Clinical trial NCT01166984: AB103 Peptide Antagonist in Healthy Volunteers
Official title: Phase 1, Double Blind, Placebo-Controlled, Dose Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Clinical Trial of AB103, A Peptide Antagonist in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteer Safety Study
Keywords: sepsis
septic shock
Lead sponsor: Atox Bio Ltd
Sponsor class: INDUSTRY
First posted: 2010-07-21
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number Adverse Events (AEs)
timeFrame: 2 weeks
measure: Number of Serious Adverse Events (SAEs)
timeFrame: 2 weeks
measure: Number of Dose-limiting Toxicities (DLTs)
timeFrame: 2 weeks
Secondary outcomes:
measure: Area Under the Plasma Concentration-time Curve (AUC)
timeFrame: 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.
measure: Cmax
timeFrame: 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.
measure: Apparent Terminal Plasma Half-life (T1/2)
timeFrame: 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.
measure: Clearance (CL)
timeFrame: 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.
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
Study officials:
affiliation: University of Maryland, College Park
name: Alan Cross, MD
role: PRINCIPAL_INVESTIGATOR
References: