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Evaluation of Anti-Hemagglutinin (Anti-HA) Antibodies as Protection From the Flu in Healthy People

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ClinicalTrials.gov Identifier: NCT01971255
Recruitment Status : Completed
First Posted : October 29, 2013
Results First Posted : April 24, 2017
Last Update Posted : April 24, 2017
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Tracking Information
First Submitted Date  ICMJE October 23, 2013
First Posted Date  ICMJE October 29, 2013
Results First Submitted Date  ICMJE October 20, 2016
Results First Posted Date  ICMJE April 24, 2017
Last Update Posted Date April 24, 2017
Study Start Date  ICMJE September 2013
Actual Primary Completion Date September 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2017)
Number of Patients With Mild to Moderate Influenza Disease (MMID) [ Time Frame: Within 10 days of inoculation ]
This was determined by presence of the combination of symptoms of influenza and presence of a positive clinical test for influenza. If both were present then the participant had positive MMID.
Original Primary Outcome Measures  ICMJE
 (submitted: October 23, 2013)
Viral shedding detected by positive diagnostic test from a nasal wash or swab as well as clinical symptoms. [ Time Frame: 2 years ]
Change History Complete list of historical versions of study NCT01971255 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2017)
  • Clinical Disease Severity Score [ Time Frame: Within 28 days after inoculation ]
    This was measured using a validated participant directed questionnaire called FLUPRO. This is then scored daily with a range of score from 0-185. The total score is the sum of all time points the questionnaire is given, which is 16 time points. Therefore the total score range is from 0-2960. 0 would represent no symptoms over the 16 time points while 2960 would represent maximum symptoms and perceived severity at all 16 time points.
  • Duration of Shedding (Days) [ Time Frame: Within 14 days of inoculation ]
    The number of days total from the time a participant had the first positive test for influenza to their last positive test.
  • Duration of Symptoms (Days) [ Time Frame: within 68 days after inoculation ]
    The number of days a participant experienced any influenza symptoms
  • Number of Symptoms [ Time Frame: within 68 days after inoculation ]
    A simple count of the number of unique influenza symptoms the participant experienced.
  • Number of Participants With Influenza Symptoms [ Time Frame: within 68 days after inoculation ]
    This was determined by the presence or absence of influenza symptoms.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluation of Anti-Hemagglutinin (Anti-HA) Antibodies as Protection From the Flu in Healthy People
Official Title  ICMJE Evaluation of Anti-Hemagglutinin Antibodies as a Correlate of Protection in an H1N1 Influenza Healthy Human Challenge Model
Brief Summary

Background:

- Researchers want to know if a certain type of antibody in the blood affects whether people get influenza (the flu). They will study 2 different groups with different levels of anti-HA antibodies and expose them to the flu virus. They will study how the flu develops in a healthy person. This may lead to future studies to develop new vaccines and treatments for the flu.

Objective:

- To study how people can be protected from flu infection.

Eligibility:

- Healthy volunteers 18 to 50 years of age.

Design:

  • Participants will be screened through the use of a medical history, physical exam, and laboratory tests.
  • Groups of 7 participants will stay in an isolation unit in a hospital for at least 9 days with no visitors.
  • Participants will be screened again upon admission. They will also have:
  • ECG: soft electrodes will be stuck to the skin. A machine will record the heart s electrical signals.
  • Echocardiogram: a small probe will be held to the chest to take pictures of the heart.
  • Lung tests: participants will blow into a machine.
  • They will also have nasal fluid collected. This will be done either with a swab or with a tube of water washing out the nose. This will be done once every day.
  • The flu virus will be sprayed into the participant s nose. This will be done only once.
  • Participants will complete a questionnaire on day 1 and twice a day after that for 14 days.
  • A medical team will watch participants 24 hours a day. They will go home after 2 days of negative flu tests.
  • Participants will have 4 follow-up visits over 8 weeks.
Detailed Description

The high morbidity and mortality associated with both pandemic and seasonal influenza, and the threat of new pandemic strains emerging, continues to keep influenza at the forefront of infectious disease and public health research. Mean annual estimates of influenza deaths due to seasonal influenza alone, attributes 36,000 deaths in the US and 250,000 to 500,000 deaths in industrialized countries to influenza. Pandemics can have an even more devastating effect, and we must continue to be prepared by making attempts to reduce the public health impact of this important virus.

Currently, influenza vaccination is the cornerstone of prophylaxis and most effective method available to reduce the impact of influenza on the world s population each year. Data from the 2013 influenza season suggest that current seasonal vaccines held to these standards are greatly underperforming especially in those that really need protection such as the elderly, young, and infirmed.

Multiple factors could play a role in defining the true correlates of protection to influenza infection and disease and many of these factors are yet to be clearly defined. In our own influenza challenge study, protocol 12-I-0077, we have clearly seen evidence that not everyone with a low HAI titer is susceptible to influenza, and that there must be other factors protecting certain individuals. There are many examples like this that demonstrate that there may be much more to immune protection to influenza than just anti-HA antibodies.

Live virus challenge studies have played an important role in defining the correlates of protection of influenza in the past, and we believe they can continue to do so in the future. Since the last time a wild-type influenza challenge has been performed to investigate correlates of protection over 20 years ago, many new scientific tools and a significant increase in knowledge of the immune system have developed. In this study we will enroll participants at different hemagglutinin inhibition titer levels and evaluate this as a correlate of protection to the 2009 H1N1 while exploring the other possible correlates of protection that may be identified. This study represents the first opportunity to examine the correlates of protection of influenza in a fully validated and described wild-type virus challenge model. We believe that studies like this are an ideal use of a wild-type influenza challenge study and can lead to intelligent universal vaccine design as well as a basis to begin evaluating novel vaccine strategies in wild-type challenge studies in the future.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Influenza
Intervention  ICMJE Biological: Ca/04/2009/H1N1r Challenge Virus
The human challenge virus will be administered intranasally to each participant using a nasal sprayer. A total volume of up to 1 mL of virus will be administered.
Study Arms  ICMJE
  • Experimental: High Titer (HAI > or = 1:40)
    Subjects with prechallenge hemagglutination inhibition (HAI) titers of ≥1:40 were assigned to this group. The human challenge virus, Ca/04/2009/H1N1r Challenge Virus, will be administered intranasally to each participant using a nasal sprayer. A total volume of up to 1 mL of virus will be administered.
    Intervention: Biological: Ca/04/2009/H1N1r Challenge Virus
  • Experimental: Low Titer (HAI < 1:40)
    Subjects with prechallenge hemagglutination inhibition (HAI) titers of <1:40 were assigned to this group. The human challenge virus, Ca/04/2009/H1N1r Challenge Virus, will be administered intranasally to each participant using a nasal sprayer. A total volume of up to 1 mL of virus will be administered.
    Intervention: Biological: Ca/04/2009/H1N1r Challenge Virus
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 17, 2015)
74
Original Estimated Enrollment  ICMJE
 (submitted: October 23, 2013)
200
Actual Study Completion Date  ICMJE September 2015
Actual Primary Completion Date September 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

-INCLUSION CRITERIA:

  1. Greater than or equal to 18 and less than or equal to 50 years of age.
  2. Agrees to not use tobacco products during participation in this study.
  3. Willingness to remain in isolation for the duration of viral shedding (at a minimum 9 days) and to comply with all study requirements.
  4. A female participant is eligible for this study if she is not pregnant or breast feeding and 1 of the following:

    • Of nonchildbearing potential (i.e., women who have had a hysterectomy or tubal ligation or are postmenopausal, as defined by no menses in greater than or equal to 1 year).
    • Of childbearing potential but agrees to practice effective contraception or abstinence for 4 weeks prior to and 8 weeks after administration of the influenza challenge virus. Acceptable methods of contraception include 1 or more of the following: 1) male partner who is sterile prior to the female participant s entry into the study and is the sole sexual partner for the female participant; 2) implants of levonorgestrel; 3) injectable progestogen; 4) an intrauterine device with a documented failure rate of < 1%; 5) oral contraceptives; and 6) double barrier methods including diaphragm or condom with a spermicide.
  5. Willing to have samples stored for future research.
  6. Prechallenge serum hemagglutination inhibition (HAI) titer against the challenge virus of greater than or equal to 1:40 or less than or equal to 1:10 during a screening visit in protocol #11-I-0183
  7. HIV uninfected.

EXCLUSION CRITEIRA:

  1. Presence of self-reported or medically documented significant medical condition including but not limited to:

    1. Chronic pulmonary disease (e.g., asthma, emphysema).
    2. Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure, cardiac surgery, ischemic heart disease, known anatomic defects).
    3. Chronic medical conditions requiring close medical follow-up or hospitalization during the past 5 years (e.g., diabetes mellitus, renal dysfunction, hemoglobinopathies).
    4. Immunosuppression or ongoing malignancy.
    5. Neurological and neurodevelopmental conditions (e.g., cerebral palsy, epilepsy, stroke, seizures).
    6. Postinfectious or postvaccine neurological sequelae.
  2. Have close or household (i.e., share the same apartment or house) high-risk contacts including but not limited to:

    1. Persons greater than or equal to 65 years of age.
    2. Children less than or equal to 5 years of age.
    3. Residents of nursing homes.
    4. Persons of any age with significant chronic medical conditions such as:

      • Chronic pulmonary disease (e.g., asthma).
      • Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure, cardiac surgery, ischemic heart disease, known anatomic defects).
      • Contacts who required medical follow-up or hospitalization during the past 5 years because of chronic metabolic disease (e.g., diabetes mellitus, renal dysfunction, hemoglobinopathies).
      • Immunosuppression or cancer.
      • Neurological and neurodevelopmental conditions (e.g., cerebral palsy, epilepsy, stroke, seizures).
      • Individuals who are receiving long-term aspirin therapy.
      • Women who are pregnant or who are trying to become pregnant.
  3. Individual with body mass index (BMI) less than or equal to 18.5 and greater than or equal to 40.
  4. Smokes more than 4 cigarettes or other tobacco products on weekly basis.
  5. Complete blood count (CBC) with differential outside of the NIH DLM normal reference range and deemed clinically significant by the PI.
  6. Chemistries in the acute care, mineral, and/or hepatic panels, and/or any of the following: lactate dehydrogenase, uric acid, creatine kinase, and total protein outside of the NIH DLM normal reference range and deemed clinically significant by the PI.
  7. Neutropenia below 1,500 cells/mm(3) (Grade 2 or greater)
  8. Urinalysis outside of the NIH DLM normal reference range and deemed clinically significant by the PI.
  9. Clinically significant abnormality on electrocardiogram.
  10. Clinically significant abnormality as deemed by the PI on echocardiographic testing.
  11. Clinically significant abnormality as deemed by the PI on the Pulmonary Function Test (PFT).
  12. Recent acute illness within 1 week of admission to the isolation facility.
  13. Known allergy to treatments for influenza (including but not limited to oseltamivir, nonsteroidals).
  14. Known allergy to 2 or more classes of antibiotics (e.g., penicillins, cephalosporins, fluoroquinolones, or glycopeptides).
  15. Receipt of blood or blood products (including immunoglobulins) within 3 months prior to enrollment.
  16. Receipt of any unlicensed drug within 3 months or 5.5 half-lives (whichever is greater) prior to enrollment.
  17. Receipt of any non-influenza related unlicensed vaccine within 6 months prior to enrollment.
  18. Self-reported or known history of current alcoholism or drug abuse, or positive urine/serum test for drugs of abuse (i.e., amphetamines, cocaine, benzodiazepines, opiates, or metabolites, but not tetrahydrocannabinol (THC) or metabolites).
  19. Self-reported or known history of psychiatric or psychological issues deemed by the PI to be a contraindication to protocol participation
  20. Known close contact with anyone known to have influenza in the past 7 days.
  21. Any condition or event that, in the judgment of the PI, is a contraindication to protocol participation or impairs the volunteer s ability to give informed consent.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01971255
Other Study ID Numbers  ICMJE 130215
13-I-0215 ( Other Identifier: United States: The National Institutes of Health )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data will be shared through the NIH data repository BTRIS - Biomedical Translational Research Information System
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Matthew J Memoli, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date March 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP