H1N1v Virus Challenge Study in Healthy Subjects

NCT04044352 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 18-0010HHSN272201300015I
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 4

Brief Summary

This is a study of a reverse-engineered, Good Manufacturing Practice (GMP) grade, antiviral-sensitive, influenza A/Bethesda/MM2/H1N1 virus (A/California/04/2009/H1N1-like) infection to assess the effect of pre-existing immunity on clinical and immunological responses. Up to 80 healthy adult subjects will undergo intranasal inoculation with A/Bethesda/MM2/H1N1 virus, and their clinical manifestations, viral shedding and immunological responses will be characterized. The Primary Objective for this study is to evaluate the association of symptomatic Reverse Transcription-Polymerase Chain Reaction (RT-PCR)-positive influenza virus infection post-challenge and pre-existing Hemagglutinin Inhibition Test (HAI) antibody titers.

Conditions

Influenza

Keywords

A/Bethesda/MM2/H1N1 Virus; Challenge; Dose Escalation; Healthy Subjects; Influenza; Live virus

Outcome Measures

Primary Outcomes (2)

• Percentage of Healthy Participants Reporting Mild-to-Moderate Influenza Disease (MMID) by Baseline A/Bethesda/MM2/H1N1 Hemagglutination Inhibition (HAI) Antibody Seroprotection Status (Titer >/= 1:40 vs. Titer < 1:40)

  Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results \>= 1:40 vs \< 1:40). MMID is a composite endpoint determined by the presence of viral shedding (detected by any approved positive RT-PCR test from a NP swab), accompanied by at least one the following symptoms occurring any time from Day 2 through Day 8; body aches or pain, chest tightness, chills, conjunctivitis, nasal congestion, sinus congestion, coryza, decreased appetite, diarrhea, dry cough, dyspnea, fatigue, fever, headache, lymphopenia, nausea, a 3% or more decrease in oxygen saturation from baseline, productive cough, rhinorrhea, sore throat, and sweats. The percentage of participants that developed MMID was calculated within each pre-challenge seroprotection status group.

  Day 2 through Day 8

• Association Between Clinical or Laboratory Manifestation of MMID and A/Bethesda/MM2/H1N1 HAI Antibodies in Serum at Baseline

  Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. MMID is a composite endpoint determined by the presence of viral shedding (detected by any approved positive RT-PCR test from a NP swab), accompanied by at least one the following symptoms occurring any time from Day 2 through Day 8; body aches or pain, chest tightness, chills, conjunctivitis, nasal congestion, sinus congestion, coryza, decreased appetite, diarrhea, dry cough, dyspnea, fatigue, fever, headache, lymphopenia, nausea, a 3% or more decrease in oxygen saturation from baseline, productive cough, rhinorrhea, sore throat, and sweats. The relationship between the level of pre-challenge HAI titer and the likelihood of developing MMID during the study challenge period (Day 2 to Day 8) was assessed via logistic regression.

  Day 2 to Day 8

Secondary Outcomes (40)

• Geometric Mean Titer (GMT) of HAI Antibody in Serum at Baseline by Infection Status

  Day -2

• GMT of HAI Antibody in Serum at Day 8 by Infection Status

  Day 8

• GMT of HAI Antibody in Serum at Day 29 by Infection Status

  Day 29

• GMT of HAI Antibody in Serum at Day 61 by Infection Status

  Day 61

• Percentage of Healthy Participants Achieving HAI Seroconversion From Baseline in Serum at Day 8 by Infection Status

  Day 8

Study Arms (1)

Group 1

EXPERIMENTAL

2 mL (approximately 5x10\^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1. N=80.

Biological: Influenza A/Bethesda/MM2/H1N1 Challenge

Interventions

Influenza A/Bethesda/MM2/H1N1 Challenge BIOLOGICAL

Reverse-genetics derived live A/California/04/2009/H1N1-like influenza virus passaged six times in Vero cells.

Group 1

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provide written informed consent prior to initiation of any study procedure.
• Are able to understand and comply with planned study procedures and be available for all study visits.
• Agree to remain an inpatient for at least seven days after challenge, and until they have no virus shedding,\* determined by qualitative RT-PCR for a minimum of two consecutive days post-challenge.
• For a minimum of seven days post-challenge (Study Day 8).
• Healthy\* males and non-pregnant, non-breastfeeding females\*\*, aged \>/= 18 and \</=49 years of age, inclusive, at enrollment.
• Females subjects of childbearing potential must agree to have a serum pregnancy test at screening, a urine pregnancy test before Chest X-Ray (CXR) performed (if more than 7 days have passed between CXR and serum pregnancy test), and a urine pregnancy test upon admission to the inpatient unit prior to CHI, and results must be negative.
• Women of childbearing potential\* must agree to use or have practiced true abstinence\*\* or use at least 1 acceptable primary form of contraception\*\*\*,\*\*\*\*.
• These criteria are applicable to females in a heterosexual relationship and child-bearing potential (i.e., the criteria do not apply to subjects in a same sex relationship).
• \*Not of child bearing potential - post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation/salpingectomy, or Essure(R) placement with history of documented radiological confirmation test at least 90 days after the procedure).
• \*\*True abstinence is 100% of time no sexual intercourse (male's penis enters the female's vagina). (Periodic abstinence \[e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception).
• \*\*\*Acceptable forms of primary contraception include monogamous relationship with a vasectomized partner who has been vasectomized for180 days or more prior to the subject receiving the influenza challenge virus, intrauterine devices, birth control pills, and injectable/implantable/insertable hormonal birth control products.
• \*\*\*\*Must use at least one acceptable primary form of contraception for at least 30 days prior to admission and at least one acceptable primary form of contraception during the remainder of the study.
• Non-habitual smoker\* of tobacco, e-cigarettes or marijuana.
• \*Non-habitual smokers are those who smoke no more than four cigarettes, other tobacco products, e-cigarettes or marijuana in a week for more than three months and agree not to smoke cigarettes, other tobacco products, e-cigarettes and/or marijuana products during participation in the study.
• No self-reported or known history of alcoholism or drug use within the last 30 days and agrees to abstain from alcohol and drugs\* for at least one week before admission and throughout the inpatient period.

You may not qualify if:

• Does not have an ongoing symptomatic condition\* for which subject has had or has ongoing medical investigations but has not yet received a diagnosis or treatment plan.
• \*e.g., ongoing fatigue without a diagnosis for symptom.
• Vital signs as follows: pulse is 47 to 99 beats per minute, inclusive; systolic blood pressure is 85 to 139 mmHg, inclusive; diastolic blood pressure is 55 to 89 mmHg, inclusive; SpO2 \>95%; RR\<18; oral temperature is less than 100.0 Degrees Fahrenheit.
• Eligibility laboratory values (White Blood Cell (WBC), Absolute Lymphocyte Count, Hemoglobin (Hgb), Platelets (PLTs), Alanine Transaminase (ALT) and Creatinine (Cr)) are within acceptable parameters.
• Body mass index (BMI) \>18.5 and \<35 kg/m\^2 at screening.
• Other screening tests (ECG and CXR) are within normal reference range or not deemed clinically significant by the PI or appropriate sub-investigator\*.
• \*Designated clinician licensed to make medical diagnoses and listed on the Form FDA 1572.
• Negative test for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) at screening blood draw.
• Negative respiratory virus panel by BIOFIRE(R) FILMARRAY(R) respiratory panel by bioMérieux or by Luminex xTAG (R) on Day (-2), and Day (-1).
• Female subject who has a positive pregnancy test on screening or admission, is breastfeeding or planning to become pregnant from 30 days prior to challenge through the end of the study.
• Presence of self-reported or medically documented significant medical or psychiatric condition(s)\*.
• \*Significant medical or psychiatric conditions include but are not limited to:
• Respiratory disease (e.g., chronic obstructive pulmonary disease (COPD), asthma) requiring daily medications (Asthma medications: inhaled, oral, or intravenous (IV) corticosteroids, leukotriene modifiers, long and short acting beta agonists, theophylline, ipratropium, biologics) currently or any treatment of respiratory disease exacerbations (e.g., asthma exacerbation) in the last 5 years
• Presence of any febrile illness or symptoms suggestive of a respiratory infection within two weeks prior to Controlled Human Infection (CHI).
• Significant cardiovascular disease (e.g., congestive heart failure, cardiomyopathy, ischemic heart disease) or history of myocarditis or pericarditis as an adult.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (4)

University of Maryland Baltimore - School of Medicine - Medicine

Baltimore, Maryland, 21201-1509, United States

Location

Saint Louis University - Center for Vaccine Development

St Louis, Missouri, 63104-1015, United States

Location

Duke Human Vaccine Institute - Duke Vaccine and Trials Unit

Durham, North Carolina, 27704, United States

Location

Cincinnati Children's Hospital Medical Center - Infectious Diseases

Cincinnati, Ohio, 45229-3039, United States

Location

Related Publications (1)

• Ortiz JR, Bernstein DI, Hoft DF, Woods CW, McClain MT, Frey SE, Brady RC, Bryant C, Wegel A, Frenck RW, Walter EB, Abate G, Williams SR, Atmar RL, Keitel WA, Rouphael N, Memoli MJ, Makhene MK, Roberts PC, Neuzil KM. A Multicenter, Controlled Human Infection Study of Influenza A(H1N1)pdm09 in Healthy Adults. J Infect Dis. 2023 Aug 11;228(3):287-298. doi: 10.1093/infdis/jiad021.

  PMID: 36702771 DERIVED

MeSH Terms

Conditions

Influenza, Human

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Kathleen M. Neuzil, MD, MPH
• Organization: University of Maryland School of Medicine

kneuzil@som.umaryland.edu

410-706-4946

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 1, 2019
• First Posted: August 5, 2019
• Study Start: October 22, 2019
• Primary Completion: March 2, 2020
• Study Completion: March 2, 2020
• Last Updated: April 28, 2021
• Results First Posted: April 28, 2021

Record last verified: 2020-12-29

Locations

US (4)