A Study to Determine the Safety of AV-1, an Antibody Being Developed for Treatment of Dengue, in Healthy Volunteers

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1a, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Determine the Safety and Pharmacokinetics of AV-1 in Healthy Male and Female Adult Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: AV-1
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be in good health at Screening (reaffirmed at Check-in): Good health is defined by the absence of a medical condition described in the exclusion criteria of the study protocol, and based on screening medical history, physical examination, vital signs, and 12-lead electrocardiogram (ECG). If the subject has another current, ongoing chronic medical condition, the condition cannot: (i) Be first diagnosed within 3 months of enrollment; or (ii) Be a pre-existing medical condition that is not exclusionary but has worsened in terms of clinical outcome within 3 months of enrollment; or (iii) Involve the need for medication that may pose a risk to the subject's safety or impede assessment of adverse events (AEs) or anti-AV-1 antibody response if they participate in the study. Women who are not pregnant and/or not lactating. Female subjects, including postmenopausal women and surgically sterile women, must have a negative serum pregnancy test at Screening, Check-in and on admission to the study facility. Female subjects must fulfill one of the following criteria: Postmenopausal women must have had ≥ 12 months of spontaneous amenorrhea with follicle-stimulating hormone concentration consistently ≥40 mIU/mL and must have a negative pregnancy test result at Screening and Check-in. Surgically sterile women - those who have had a hysterectomy, bilateral ovariectomy (oophorectomy), or bilateral tubal ligation, must provide documentation of the procedure and must have a negative pregnancy test at Screening and Check-in. Must be willing to not engage in sexual intercourse from Check-in until the final follow-up visit on Day 120 (± 5 days). Must be willing to use an acceptable method of birth control until the final follow-up visit on Day 120 (± 5 days) as defined by the protocol and Investigator. Male subjects who are biologically capable of fathering children must agree and commit to using an adequate form of double-barrier contraception, and refrain from sperm donation from Check-in until the final follow-up visit on Day 120 (± 5 days). A male subject is considered capable of fathering children even if his sexual partner is sterile or using contraceptives. Body Mass Index between 18.5 and 29.9 kg/m^2 inclusive. Must not have traveled outside the USA within 60 days prior to Check-in, and agree not to travel outside the USA through the final follow-up visit on Day 120 (± 5 days). Must agree to abide by study restrictions and be willing to sign an informed consent form (ICF). Exclusion Criteria: Any significant medical condition that, in the opinion of the Investigator or Sponsor, would interfere with the subject's ability to participate in the study or increase the risk of participating for that subject, based on the Investigator's Brochure and the safety profile of AV-1. Subject has one or more symptoms of a urinary tract infection (e.g. dysuria, frequent, urgency, or suprapubic pain) at Screening or Check-in. Has certain abnormal12-lead ECG (electrocardiogram) results according to the protocol, as assessed by the Investigator. Has abnormal laboratory values for certain hematology, serum chemistry, coagulation, or urinalysis tests according to the protocol, as assessed by the Investigator. Is positive for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus (HIV) antibody types 1 and 2 within 35 days of enrollment. Has any psychiatric condition or history of psychiatric condition that, in the opinion of the Investigator or Sponsor, would interfere with the subject's ability to participate in the study or increase the risk of participation for that subject. Is unwilling to abstain from alcohol, caffeine-, or other xanthine-containing foods or beverages, tobacco or nicotine-containing products, and all bergamottin-containing fruits and fruit juices (e.g. Seville oranges, grapefruit/grapefruit juice, pomelos, pomegranate/pomegranate juice, cranberries/cranberry juice) 72 hours prior to Check-in, through discharge on Day 5 of the study. Is unwilling to abstain from strenuous exercise 7 days before Check-in through Day 15 of the study. Has a history of alcoholism or drug/chemical abuse within 6 months prior to Check-in. Has excessive alcohol consumption (regular alcohol intake >21 units per week for male subjects and >14 units of alcohol per week for female subjects) (1 unit is equal to approximately 1/2 pint [200 mL] beer, 1 small glass [100 mL] wine, or 1 measure [25 mL] spirits). Has a positive urine drug screen at Screening or Check-in. Has a positive cotinine urine test at Check-in. Has any confirmed or suspected immunosuppressive or immunodeficient condition, including but not limited to human immunodeficiency virus infection, or use of anti-cancer chemotherapy or radiation therapy (cytotoxic) in the 3 years prior to Screening. Provides verbal history of vaccination with a licensed or investigational flavivirus vaccine for any of the following diseases: Zika virus, dengue virus (DENV), yellow fever virus, Japanese encephalitis virus, West Nile virus, St. Louis encephalitis virus, or tick-borne encephalitis virus; or reportedly diagnosed with a flavivirus infection or disease. Plans to receive a licensed flavivirus vaccine or participate in flavivirus vaccine trial during the study. Is positive for DENV or West Nile virus by immunoglobulin M, or immunoglobulin G, or Zika by immunoglobulin M serology testing within 35 days of enrollment. Has a history of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee). Has had major surgery within 3 months prior to Screening or plans to have major surgery during the study through the final follow-up on Day 120 (± 5 days). Has been treated for a medical condition with a licensed monoclonal or polyclonal antibody in the past; or dosed in a clinical study involving administration of an investigational monoclonal or polyclonal antibody in the 18 months prior to study drug administration on Day 1. Has received an investigational drug within 28 days of study drug administration on Day 1. Has used any prohibited medication within 30 days prior to Check-in, or plans to use prohibited medication during the study. Prohibited medications include: Immunosuppressive drugs, immune modulators (except acetaminophen), oral corticosteroids, inhaled or intranasal steroids (<800 µg/day beclomethasone is acceptable), and anti-neoplastic agents. Topical steroids are acceptable. Has received or plans to receive any live vaccination, experimental or otherwise, within 28 days prior to or after Day 1 of the study; and receipt or planned receipt of an inactivated vaccination (or any COVID-19 vaccine), experimental or otherwise, within 14 days prior to or after Day 1 of the study. Has received blood products within 60 days prior to Check-in. Has donated or lost more than 450 mL of blood or plasma within 56 days of study drug infusion on Day 1. The subject must also agree to refrain from donating blood or plasma during the study. Has poor peripheral venous access. Previously completed or withdrawn from this study. Is a current clinical site staff paid entirely or partially by the contractor for this trial, or staff who are supervised by the Investigator or subinvestigators. In the opinion of the Investigator (or designee), the subject is not suitable for entry into the study. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AV-1 30 mg<br>Participants received a single intravenous (IV) infusion (infusion duration: 1 hour) of AV-1 30 mg on Day 1. | Drug: AV-1<br>* Single dose, administered by IV infusion (volume: 250 mL)<br>|
| Experimental: AV-1 90 mg<br>Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 90 mg on Day 1. | Drug: AV-1<br>* Single dose, administered by IV infusion (volume: 250 mL)<br>|
| Experimental: AV-1 250 mg<br>Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 250 mg on Day 1. | Drug: AV-1<br>* Single dose, administered by IV infusion (volume: 250 mL)<br>|
| Experimental: AV-1 500 mg<br>Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 500 mg on Day 1. | Drug: AV-1<br>* Single dose, administered by IV infusion (volume: 250 mL)<br>|
| Experimental: AV-1 1000 mg<br>Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 1000 mg on Day 1. | Drug: AV-1<br>* Single dose, administered by IV infusion (volume: 250 mL)<br>|
| Placebo Comparator: Placebo<br>Participants received a single IV infusion (infusion duration: 1 hour) of placebo matched to AV-1 on Day 1. | Drug: Placebo<br>* 0.9% sterile saline. Administered by IV infusion (volume: 250 mL)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | Baseline up to Day 120 (± 5 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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]). | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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 | Baseline, Days 29 (±2), 85 (±5), and 120 (±5) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers, Monoclonal antibody, AV-1, Safety, Dengue