H1N1v Virus Challenge Study in Healthy Subjects

NCT ID: NCT04044352

Last Updated: 2021-04-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 76 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-22
• Study Completion Date: 2020-03-02

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.

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 from study subjects at baseline and post-challenge; 2) To describe serum HAI and MN 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 determine the frequency of serious adverse events (SAE) post-challenge.

Conditions

Influenza

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Influenza A/Bethesda/MM2/H1N1 Challenge

Intervention Type: BIOLOGICAL

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

Interventions

Influenza A/Bethesda/MM2/H1N1 Challenge

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

Intervention Type: BIOLOGICAL

Eligibility 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.

• 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).

Exclusion Criteria

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 (PLTs), Alanine Transaminase (ALT) and Creatinine (Cr)) are within acceptable parameters.

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 human immunodeficiency virus (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).

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 49 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of Maryland Baltimore - School of Medicine - Medicine

Baltimore, Maryland, United States

Saint Louis University - Center for Vaccine Development

St Louis, Missouri, United States

Duke Human Vaccine Institute - Duke Vaccine and Trials Unit

Durham, North Carolina, United States

Cincinnati Children's Hospital Medical Center - Infectious Diseases

Cincinnati, Ohio, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 36702771 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

HHSN272201300015I

Identifier Type: -

Identifier Source: secondary_id

18-0010

Identifier Type: -

Identifier Source: org_study_id