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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04273217
Recruitment Status : Completed
First Posted : February 18, 2020
Results First Posted : October 31, 2022
Last Update Posted : October 31, 2022
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AbViro LLC

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: AV-1 Drug: Placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Official Title: 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
Actual Study Start Date : February 4, 2020
Actual Primary Completion Date : July 8, 2021
Actual Study Completion Date : July 8, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dengue

Arm Intervention/treatment
Experimental: AV-1 30 mg
Participants received a single intravenous (IV) infusion (infusion duration: 1 hour) of AV-1 30 mg on Day 1.
Drug: AV-1
Single dose, administered by IV infusion (volume: 250 mL)

Experimental: AV-1 90 mg
Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 90 mg on Day 1.
Drug: AV-1
Single dose, administered by IV infusion (volume: 250 mL)

Experimental: AV-1 250 mg
Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 250 mg on Day 1.
Drug: AV-1
Single dose, administered by IV infusion (volume: 250 mL)

Experimental: AV-1 500 mg
Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 500 mg on Day 1.
Drug: AV-1
Single dose, administered by IV infusion (volume: 250 mL)

Experimental: AV-1 1000 mg
Participants received a single IV infusion (infusion duration: 1 hour) of AV-1 1000 mg on Day 1.
Drug: AV-1
Single dose, administered by IV infusion (volume: 250 mL)

Placebo Comparator: Placebo
Participants received a single IV infusion (infusion duration: 1 hour) of placebo matched to AV-1 on Day 1.
Drug: Placebo
0.9% sterile saline. Administered by IV infusion (volume: 250 mL)




Primary Outcome Measures :
  1. Number of Participants With Clinical Laboratory Abnormalities Reported as Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline up to Day 120 (± 5 days) ]
    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.

  2. Number of Participants With Physical Examination Abnormalities Reported as TEAEs [ Time Frame: Baseline up to Day 120 (± 5 days) ]
    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.

  3. Number of Participants With Vital Sign Abnormalities Reported as TEAEs [ Time Frame: Baseline up to Day 120 (± 5 days) ]
    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.

  4. Number of Participants With 12-lead Electrocardiogram (ECG) Abnormalities Reported as TEAEs [ Time Frame: Baseline up to Day 120 (± 5 days) ]
    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.

  5. Number of Participants With TEAEs [ Time Frame: Baseline up to Day 120 (± 5 days) ]

    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.


  6. Number of Participants With Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Day 120 (± 5 days) ]

    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.


  7. Number of Participants by Severity of AEs [ Time Frame: Baseline up to Day 120 (± 5 days) ]

    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.



Secondary Outcome Measures :
  1. Area Under the Serum Concentration-time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-infinity) of AV-1 [ 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 ]
    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]).

  2. AUC From Time 0 to 48 Hours Postdose (AUC0-48) of AV-1 [ 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 ]
    AUC0-48 was calculated using the linear trapezoidal rule method.

  3. AUC From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) [ 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 ]
    AUC0-tlast was calculated using the linear trapezoidal method.

  4. Maximum Observed Serum Concentration (Cmax) of AV-1 [ 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 ]
    Cmax is defined as maximum observed serum drug concentration.

  5. Time to Reach Cmax (Tmax) of AV-1 [ 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 ]
    Tmax is defined as Time to reach maximum serum concentration following drug administration.

  6. Apparent Terminal Half-life (t1/2) of AV-1 [ 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 ]
    t1/2 is defined as terminal half-life, calculated as: ln(2)/ λz, where λz is apparent terminal elimination rate constant.

  7. Total Serum Clearance (CL) of AV-1 [ 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 was calculated as dose divided by AUC0-infinity.

  8. Volume of Distribution During the Terminal Phase (Vz) of AV-1 [ 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 was calculated as dose divided by (AUC0-infinity*λz).

  9. Number of Participants With Detectable Anti-AV-1 Antibody [ Time Frame: Baseline, Days 29 (±2), 85 (±5), and 120 (±5) ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subject must be in good health at Screening (reaffirmed at Check-in):

    1. 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).
    2. 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:

    1. 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.
    2. 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.
    3. Must be willing to not engage in sexual intercourse from Check-in until the final follow-up visit on Day 120 (± 5 days).
    4. 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04273217


Locations
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United States, Texas
PPD Austin Clinic, 7551 Metro Center Drive, Suite 200
Austin, Texas, United States, 78744
Sponsors and Collaborators
AbViro LLC
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Principal Investigator: Rebecca Wood-Horrall, MD PPD
  Study Documents (Full-Text)

Documents provided by AbViro LLC:
Study Protocol  [PDF] April 23, 2021
Statistical Analysis Plan  [PDF] March 8, 2021

Additional Information:
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Responsible Party: AbViro LLC
ClinicalTrials.gov Identifier: NCT04273217    
Other Study ID Numbers: AV1-PPD-0005
DMID 18-0016 ( Other Identifier: DMID Protocol Number )
HHSN272201600028C ( Other Identifier: NIAID Contract Number )
First Posted: February 18, 2020    Key Record Dates
Results First Posted: October 31, 2022
Last Update Posted: October 31, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AbViro LLC:
Healthy volunteers
Monoclonal antibody
AV-1
Safety
Dengue