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H1N1v Virus Challenge Study in Healthy Subjects

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ClinicalTrials.gov Identifier: NCT04044352
Recruitment Status : Recruiting
First Posted : August 5, 2019
Last Update Posted : November 1, 2019
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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.

Condition or disease Intervention/treatment Phase
Influenza Biological: Influenza A/Bethesda/MM2/H1N1 Challenge Phase 1

Detailed Description:
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. This proposed study will establish a H1N1 influenza virus controlled human infection (CHI) model at the National Institute of Allergy and Infectious Diseases (NIAID) Division of Microbiology and Infectious Diseases (DMID)-sponsored Vaccine and Treatment Evaluation Units (VTEU) clinical study sites. The model has been developed and used by NIAID Division of Intramural Research. The proposed study will expand US research capacity to perform influenza CHI studies to advance the understanding of influenza pathogenesis and novel vaccine research and development. 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. The Secondary Objectives for this study are: 1) To describe viral recovery by quantitative RT-PCR and/or viral culture from study subjects at baseline and post-challenge; 2) To describe serum antibody responses post-challenge in healthy subjects by infection status; 3) To evaluate the association of asymptomatic RT-PCR-positive influenza virus infection (viral shedding) post-challenge and pre-existing HAI antibody titers; 4) To evaluate the association of symptomatic RT-PCR-negative status post-challenge and pre-existing HAI antibody titers; 5) To evaluate the association of symptomatic RT-PCR-positive influenza virus infection, asymptomatic RT-PCR-positive influenza virus infection (viral shedding only) and symptomatic RT-PCR-negative illness and pre-existing neuraminidase inhibition (NAI) antibody titers; 6) To determine the frequency of serious adverse events (SAE) post-challenge.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Controlled Human Infection Study of Influenza A/Bethesda/MM2/H1N1 Virus (A/California/04/2009/H1N1-like) in Healthy Subjects to Assess the Effect of Pre-Existing Immunity on Symptomatic Influenza Virus Infection
Actual Study Start Date : October 7, 2019
Estimated Primary Completion Date : May 8, 2020
Estimated Study Completion Date : May 8, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Flu Flu Shot

Arm Intervention/treatment
Experimental: Group 1
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
Reverse-genetics derived live A/California/04/2009/H1N1-like influenza virus passaged six times in Vero cells.




Primary Outcome Measures :
  1. Clinical or laboratory manifestation of Mild-to-Moderate Influenza Disease (MMID) [ Time Frame: Day 1 through Day 8 ]
  2. Geometric Mean Titer (GMT) of A/Bethesda/MM2/H1N1 hemagglutination inhibition (HAI) antibodies in serum [ Time Frame: Day 1 through Day 8 ]
  3. Presence of viral shedding detected by positive Reverse Transcription - Polymerase Chain Reaction (RT-PCR) test from Nasopharyngeal (NP) [ Time Frame: Day 1 through Day 8 ]

Secondary Outcome Measures :
  1. Change in Geometric Mean Titer (GMT) of Hemagglutinin Inhibition (HAI) antibody in serum from baseline [ Time Frame: Day 8 through Day 61 ]
  2. Change in Geometric Mean Titer (GMT) of Microneutralization (MN) antibody in serum from baseline [ Time Frame: Day 8 through Day 61 ]
  3. Change in Geometric Mean Titer (GMT) of Neuraminidase Inhibition (NAI) antibody in serum from baseline [ Time Frame: Day 8 through Day 61 ]
  4. Changes in duration of viral shedding in Nasal Lavage Fluid (NLF) from baseline [ Time Frame: Day 2 through Day 8 ]
  5. Changes in duration of viral shedding in Nasopharyngeal (NP) swab from baseline [ Time Frame: Day 2 through Day 8 ]
  6. Changes in frequency of viral shedding in Nasal Lavage Fluid (NLF) from baseline [ Time Frame: Day 2 through Day 8 ]
  7. Changes in frequency of viral shedding in Nasopharyngeal (NP) swab from baseline [ Time Frame: Day 2 through Day 8 ]
  8. Changes in Geometric Mean Titer (GMT) of A/Bethesda/MM2/H1N1 Hemagglutination Inhibition (HAI) antibodies in serum associated with asymptomatic viral shedding by Reverse Transcription - Polymerase Chain Reaction (RT-PCR) from baseline [ Time Frame: Day 1 through Day 8 ]
  9. Changes in Geometric Mean Titer (GMT) of A/Bethesda/MM2/H1N1 Hemagglutination Inhibition (HAI) antibodies in serum associated with development of any Flu-PRO symptoms post-challenge without influenza virus detection from baseline [ Time Frame: Day 1 through Day 8 ]
  10. Changes in Geometric Mean Titer (GMT) of A/Bethesda/MM2/H1N1 Neuraminidase Inhibition (NAI) antibodies in serum associated with positive infection status, by symptom/shedding status, from baseline [ Time Frame: Day 1 through Day 8 ]
  11. Changes in magnitude of viral shedding in Nasal Lavage Fluid (NLF) from baseline [ Time Frame: Day 2 through Day 8 ]
  12. Changes in magnitude of viral shedding in Nasopharyngeal (NP) swab from baseline [ Time Frame: Day 2 through Day 8 ]
  13. Changes in timing of viral shedding in Nasal Lavage Fluid (NLF) from baseline [ Time Frame: Day 2 through Day 8 ]
  14. Changes in timing of viral shedding in Nasopharyngeal (NP) swab from baseline [ Time Frame: Day 2 through Day 8 ]
  15. Frequency of Serious Adverse Events (SAEs) [ Time Frame: Day 1 through Day 91 ]
  16. Percentage of healthy subjects achieving HAI seroconversion (either a pre-challenge titer < 1:10 and a post-challenge titer > / = 1:40 or a pre-challenge titer > / = 1:10 and a minimum 4-fold rise in post-challenge antibody titer) in serum from baseline [ Time Frame: Day 8 through Day 61 ]
  17. Percentage of healthy subjects achieving MN seroconversion (either a pre-challenge titer < 1:10 and a post-challenge titer > / = 1:40 or a pre-challenge titer > / = 1:10 and minimum 4-fold rise in post-challenge antibody titer) in serum from baseline [ Time Frame: Day 8 through Day 61 ]
  18. Percentage of healthy subjects achieving NAI seroconversion (either a pre-challenge titer < 1:10 and a post-challenge titer > / = 1:40 or a pre-challenge titer > / = 1:10 and minimum 4-fold rise in post-challenge antibody titer) in serum from baseline [ Time Frame: Day 8 through Day 61 ]


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Ages Eligible for Study:   18 Years to 49 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Provide written informed consent prior to initiation of any study procedure.
  2. Are able to understand and comply with planned study procedures and be available for all study visits.
  3. 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).
  4. Healthy* males and non-pregnant, non-breastfeeding females**, aged > / = 18 and < / =49 years of age, inclusive, at enrollment.

    *Good health is defined in inclusion criteria 10.

    • 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.
  5. 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.

  6. 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.

  7. 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.

    *Including forms of marijuana not included in criterion 6.

  8. Negative drug urine toxicology result on screening (i.e., amphetamines, cocaine, and opiates) and on admission to the challenge unit (i.e., amphetamines, cocaine, opiates, and cannabinoids).
  9. Agree not to use the listed* prescription or over-the-counter medications within 7 days prior to inpatient stay and through inpatient stay, unless approved by the investigator.

    *Oseltamivir, zanamivir, peramivir, baloxavir marboxil, amantadine (generic) and rimantadine (Flumadine and generic), aspirin, intranasal steroids, decongestants, antihistamines, and other non-steroidal anti-inflammatory drugs (NSAIDs).

  10. In good health* and not have clinically significant medical, psychiatric, chronic or intermittent health conditions including those listed in the Subject Exclusion Criteria.

    *Good health, as determined by medical history, medication use and physical examination to evaluate ongoing chronic medical or psychiatric diagnoses or conditions, defined as those that have been present for at least 90 days, which would not affect the assessment of the safety of subjects or the immunogenicity of challenge. These medical diagnoses or conditions should be stable for the last 90 days (no hospitalizations, emergency room (ER) or urgent care for condition (excluding musculoskeletal conditions) and not listed in the Subject Exclusion Criteria. Subjects may be on medications only if the condition or disease is stable and not deteriorating, if the medical intervention (such as device or medication) was not available during the maximal inpatient period of time, medications are not listed in the Subject Exclusion Criteria and pose no additional risk to subject safety or assessment of adverse events. This also includes no change in prescription medication, dose or frequency as a result of new symptoms or deterioration of the medical diagnosis or condition in the 90 days prior to enrollment. Any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome (e.g., lowering of the dosage or frequency), as determined by the site principal investigator (PI) or designated clinician licensed to make medical diagnoses and listed on Form FDA 1572, will not be considered a deviation of this inclusion criterion.

  11. 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.

  12. 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.
  13. Eligibility laboratory values (White Blood Cell (WBC), Absolute Lymphocyte Count, Hemoglobin (Hgb), Platelets, Alanine Transaminase (PLTs) and Creatinine (Cr)) are within acceptable parameters: (Hematology) WBC 103/UL (3.70 -11.00), Absolute Lymphocyte count/103/UL ( > / = 1000), Hgb g/dL (Female) ( > / = 11.0), Hgb g/dL (Male) ( > / = 12.5), Platelets cell/103/UL EDTA (163 - 375), Platelets K/cu mm Citrate (125 - 375). (Chemistry) ALT IU/L (Female) ( < /= 43), ALT IU/L (Male) ( < / = 60), Creatinine mg/dL ( < / = 1.4).
  14. Body mass index (BMI) >18.5 and <35 kg/m^2 at screening.
  15. 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).

  16. Negative test for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) at screening blood draw.
  17. Negative respiratory virus panel by BIOFIRE(R) FILMARRAY(R) respiratory panel by bioMérieux or by Luminex xTAG(R) on Day (-2), and Day (-1).

Exclusion Criteria:

  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.
  2. 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.
    • Neurological or neurodevelopmental conditions (e.g., epilepsy, stroke, seizures, encephalopathy, focal neurologic deficits, Guillain-Barre syndrome, encephalomyelitis or transverse myelitis).
    • Ongoing malignancy or recent diagnosis of malignancy in the last five years excluding basal cell carcinoma of the skin, which is allowed.
    • An autoimmune disease.
    • An immunodeficiency of any cause.
    • A history of diabetes.
  3. Presence of immunosuppression or any medications that may be associated with impaired immune responsiveness*.

    *Including, but not limited to, corticosteroids exceeding 10 mg/day of prednisone equivalent, allergy injections, immunoglobulin, interferon, immunomodulators, cytotoxic drugs, or systemic corticosteroids or other similar or toxic drugs during the preceding 12-month period prior to screening. Low dose topical and intranasal steroid preparations used for a discrete period of time are permitted.

  4. Known allergy or intolerance to treatments for influenza (including but not limited to oseltamivir, baloxavir marboxil, acetaminophen).
  5. Known allergy to two or more classes of antibiotics (e.g., penicillins, cephalosporins, fluoroquinolones, or glycopeptides).
  6. Known allergy to excipients in the challenge virus inoculum.
  7. Receipt or planned receipt of any investigational drug/investigational vaccine/licensed vaccine within 30 days prior to the date of CHI.
  8. Prior enrollment in any influenza virus challenge study.
  9. Currently enrolled in any investigational study or intends to enroll in such a study within the ensuing study period.
  10. Receipt of any influenza vaccine six months prior to challenge or plans to receive influenza vaccine within 60 days post-challenge.
  11. History of a previous severe allergic reaction of any kind with generalized urticaria, angioedema, or anaphylaxis.
  12. Receipt of blood or blood products during the six months prior to the planned date of challenge.
  13. History of blood donation during the two months prior to the planned date of challenge and or plans to donate blood for the duration of the study.
  14. Any condition, to include medical and psychiatric conditions, that in the opinion of the Investigator, might interfere with the safety of the subject and/or study objectives.
  15. Known close contact with anyone known to have influenza 7 days prior to challenge.
  16. Acute medical condition with new prescription medication use in the last 30 days.
  17. Significant abnormality altering the anatomy of the nose/nasopharynx* clinically significant nasal deviation, or nasal/sinus surgery within 180 days prior to challenge.

    *Including significant nasal polyps.

  18. History in the last five years of chronic or frequent intermittent sinusitis.
  19. Recent history (180 days) of epistaxis or anatomic or neurologic abnormality impairing the gag reflex or contributing to aspiration.

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): NCT04044352


Contacts
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Contact: Kathleen Neuzil 14107064946 kneuzil@som.umaryland.edu

Locations
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United States, Maryland
University of Maryland Baltimore - School of Medicine - Medicine Recruiting
Baltimore, Maryland, United States, 21201-1509
United States, Missouri
Saint Louis University - Center for Vaccine Development Recruiting
Saint Louis, Missouri, United States, 63104-1015
United States, North Carolina
Duke Human Vaccine Institute - Duke Vaccine and Trials Unit Recruiting
Durham, North Carolina, United States, 27704
United States, Ohio
Cincinnati Children's Hospital Medical Center - Infectious Diseases Recruiting
Cincinnati, Ohio, United States, 45229-3039
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)

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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04044352     History of Changes
Other Study ID Numbers: 18-0010
HHSN272201300015I
First Posted: August 5, 2019    Key Record Dates
Last Update Posted: November 1, 2019
Last Verified: July 31, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
A/Bethesda/MM2/H1N1 Virus
Challenge
Dose Escalation
Healthy Subjects
Influenza
Live virus
Additional relevant MeSH terms:
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Influenza, Human
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases