AV-1 is a human monoclonal antibody (mAb) being investigated as a potential therapy for dengue, a mosquito-borne viral disease with extensive global public health impact. Globally, over 2 billion people are thought to be at risk of infection from the dengue virus and there are an estimated 390 million infections each year. Current treatment options for dengue are limited to supportive care, so a safe and effective treatment would provide substantial public health benefits. AV-1 has not previously been tested in humans. This study aims to determine the safety of AV-1 in healthy adult volunteers, when administered as a single IV infusion. The results of the study are based on the clinical study report and statistical analysis plan.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
TRIPLE
Enrollment
42
Single dose, administered by IV infusion (volume: 250 mL)
0.9% sterile saline. Administered by IV infusion (volume: 250 mL)
PPD Austin Clinic, 7551 Metro Center Drive, Suite 200
Austin, Texas, United States
Number of Participants With Clinical Laboratory Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs)
Clinical laboratory abnormalities reported as TEAEs by the investigator. Clinical laboratory abnormalities were defined as any abnormal findings in analysis of hematology, serum chemistry, coagulation, and urine parameters. A TEAE was defined as any event not present before exposure to study drug or any event already present that worsened in intensity or frequency after exposure whether or not considered drug related.
Time frame: Baseline up to Day 120 (± 5 days)
Number of Participants With Physical Examination Abnormalities Reported as TEAEs
A full physical examination included examination of skin; head, ears, eyes, nose, throat (HEENT); neck; thyroid; lungs; heart; cardiovascular; abdomen; lymph nodes; and musculoskeletal system/extremities. Focused examination included lungs, cardiovascular, abdomen, and skin. Investigator could perform targeted, symptom-directed physical examination. A TEAE was defined as any event not present before exposure to study drug or any event already present that worsened in intensity or frequency after exposure whether or not considered drug related.
Time frame: Baseline up to Day 120 (± 5 days)
Number of Participants With Vital Sign Abnormalities Reported as TEAEs
Vital sign measurements included systolic and diastolic blood pressure, oral body temperature, heart rate, and respiratory rate. A TEAE was defined as any event not present before exposure to study drug or any event already present that worsened in intensity or frequency after exposure whether or not considered drug related.
Time frame: Baseline up to Day 120 (± 5 days)
Number of Participants With 12-lead Electrocardiogram (ECG) Abnormalities Reported as TEAEs
Number of participants with abnormal 12-lead ECG reported as a TEAE of electrocardiogram QT prolonged by the investigator. A TEAE was defined as any event not present before exposure to study drug or any event already present that worsened in intensity or frequency after exposure whether or not considered drug related.
Time frame: Baseline up to Day 120 (± 5 days)
Number of Participants With TEAEs
An adverse event (AE) was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of medicinal (investigational) product. A TEAE was defined as any event not present before exposure to study drug or any event already present that worsened in intensity or frequency after exposure.
Time frame: Baseline up to Day 120 (± 5 days)
Number of Participants With Serious Adverse Events (SAEs)
An AE or suspected adverse reaction was considered an SAE if, in the view of either the Investigator or Sponsor, it resulted in any of the following outcome: * Death * A life-threatening AE * Inpatient hospitalization or prolongation of existing hospitalization * a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions * A congenital anomaly/birth defect Important medical events that did not result in death, was life-threatening, or required hospitalizations could have been considered serious when, based upon appropriate medical judgment, they jeopardized the participant and required medical or surgical intervention to prevent one of the outcomes listed in this definition.
Time frame: Baseline up to Day 120 (± 5 days)
Number of Participants by Severity of AEs
AEs were assessed by the Investigator as Mild (Grade 1), Moderate (Grade 2), or Severe (Grade 3). Mild (Grade 1): Events that were transient and required only minimal or no treatment or therapeutic intervention and did not interfere with the participants usual activities of daily living. Moderate (Grade 2): Events that were alleviated with additional specific therapeutic intervention. The event interfered with usual activities of daily living, causing discomfort but posed no significant or permanent risk of harm to the participant. Severe (Grade 3): Events interrupted usual activities of daily living, or significantly affected clinical status, or required intensive therapeutic intervention. Severe events were usually incapacitating.
Time frame: Baseline up to Day 120 (± 5 days)
Area Under the Serum Concentration-time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-infinity) of AV-1
AUC0-infinity was calculated as: AUC from time 0 to the last quantifiable concentration (AUC0-tlast) + (last observed serum drug concentration \[Ct\] / Apparent terminal elimination rate constant \[λz\]).
Time frame: Predose (within 15 minutes); at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the start of infusion; Days 5, 8, 15, 22, 29, 43, 57, 85, and 120
AUC From Time 0 to 48 Hours Postdose (AUC0-48) of AV-1
AUC0-48 was calculated using the linear trapezoidal rule method.
Time frame: Predose (within 15 minutes); at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the start of infusion
AUC From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)
AUC0-tlast was calculated using the linear trapezoidal method.
Time frame: Predose (within 15 minutes); at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the start of infusion; Days 5, 8, 15, 22, 29, 43, 57, 85, and 120
Maximum Observed Serum Concentration (Cmax) of AV-1
Cmax is defined as maximum observed serum drug concentration.
Time frame: Predose (within 15 minutes); at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the start of infusion; Days 5, 8, 15, 22, 29, 43, 57, 85, and 120
Time to Reach Cmax (Tmax) of AV-1
Tmax is defined as Time to reach maximum serum concentration following drug administration.
Time frame: Predose (within 15 minutes); at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the start of infusion; Days 5, 8, 15, 22, 29, 43, 57, 85, and 120
Apparent Terminal Half-life (t1/2) of AV-1
t1/2 is defined as terminal half-life, calculated as: ln(2)/ λz, where λz is apparent terminal elimination rate constant.
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Time frame: Predose (within 15 minutes); at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the start of infusion; Days 5, 8, 15, 22, 29, 43, 57, 85, and 120
Total Serum Clearance (CL) of AV-1
Total serum clearance was calculated as dose divided by AUC0-infinity.
Time frame: Predose (within 15 minutes); at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the start of infusion; Days 5, 8, 15, 22, 29, 43, 57, 85, and 120
Volume of Distribution During the Terminal Phase (Vz) of AV-1
Volume of distribution during the terminal phase was calculated as dose divided by (AUC0-infinity\*λz).
Time frame: Predose (within 15 minutes); at 0.5, 1 (end of infusion), 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after the start of infusion; Days 5, 8, 15, 22, 29, 43, 57, 85, and 120
Number of Participants With Detectable Anti-AV-1 Antibody
Serum samples for measurement of anti-AV-1 antibody levels were analyzed by a validated electrochemiluminescence enzyme-linked immunosorbent assay method used for detection and confirmation of pre-existing and treatment-emergent anti-AV-1 antibodies in serum samples based on the MesoScale Discovery platform that utilized labeled AV-1 for detection of anti-AV-1 antibodies and treatment-emergent antibodies. Number of participants with detectable anti-AV-1 antibody
Time frame: Baseline, Days 29 (±2), 85 (±5), and 120 (±5)