Safety and Efficacy of an H1N1 Influenza Vaccine in People With Asthma

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and the body's immune response (body's defense against disease) to an experimental H1N1 influenza vaccine in people with asthma. The study will enroll 350, and possibly up to 400 healthy adults ages 12 and older with mild, moderate, or severe asthma. Participants will be randomly assigned to 1 of 2 possible vaccine groups: group 1 will receive 15 mcg of H1N1 vaccine; group 2 will receive 30 mcg of H1N1 vaccine given as two 15 mcg injections. Both groups will receive vaccine injections on days 0 and 21. Study procedures include: medical history, physical exam, spirometry, maintaining a memory aid and, and blood sample collection. Participants will be involved in study related procedures for approximately 7 months.

Detailed Description
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A new swine-origin influenza A/H1N1 virus was recently identified as a significant cause of respiratory illness in Mexico and the United States. In response, the World Health Organization (WHO) declared a pandemic on June 11, 2009. Current data indicates that licensed seasonal influenza vaccines are not likely to provide protection against the new H1N1 virus. Development and deployment of a vaccine for the new H1N1 virus, particularly to at-risk populations, is essential. Groups at risk for influenza yearly include the elderly and those with asthma, and current guidelines from the Advisory Committee on Immunization Practices (ACIP) recommend vaccination of adults and children with asthma. Early, unpublished data on US patients hospitalized by H1N1 infection indicates that many had underlying asthma, and it is expected people with asthma will be on a priority list for H1N1 influenza vaccination. Data also indicate that increased dosage of vaccines may increase development of antibodies and that use of certain inhalers may affect immunization. This study will test the safety and immunogenicity of an unadjuvanted, inactivated H1N1 vaccine at two dosage levels in people with asthma. Participation in this study will last approximately 34 weeks. Participants will be stratified into two groups: those with mild to moderate versus those with severe asthma. All participants will be randomly assigned to receive either a high dose (30 mcg) or low dose (15 mcg) H1N1 vaccine. Both vaccine dosages will be administered in two intramuscular injections 21 days apart. Participants assigned to the higher dose (30 mcg) will receive two injections of the 15 mcg vaccine at each administration. Participants will complete study visits at entry, administration of the vaccines on Days 1 and 21, follow-ups a week after each vaccine injection, and 21 days after the second injection. Measurements at these visits will include spirometry (measurement of air entering and leaving the lungs), a questionnaire about asthma, a targeted physical examination, an adverse event and medication assessment, inspection of vaccination site, and collection of a blood sample. A urine sample will be collected for pregnancy test before each vaccination. In additions, for 8 days after each vaccination injection participants will keep a diary recording oral temperature, adverse events, asthma symptoms, and use of inhalers. These diaries will be reviewed at study visits. Participants will also receive follow-up phone calls to assess safety 60, 120, and 180 days after the last vaccine injection.

Official Title
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A Phase II Study in Patients With Asthma to Assess the Safety and Immunogenicity of an Unadjuvanted Novartis H1N1 Influenza Vaccine Administered at Two Dose Levels

Conditions
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H1N1 Influenza Virus

Intervention / Treatment
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* Biological: H1N1 vaccine high dose
* Biological: H1N1 vaccine low dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of mild/moderate or severe asthma according to Severe Asthma Research Project (SARP) definitions and either a SARP participant or having prior participation in the studies or clinics of the investigators Males and females age 12 (inclusive) and older Females of child-bearing potential must not be pregnant and must agree to practice adequate contraception that may include, but is not limited to: abstinence, monogamous relationship with vasectomized partner, barrier methods such as condoms, diaphragms, spermicides, intrauterine devices, and licensed hormonal methods during the study for at least 30 days following the last vaccination. Able to understand and comply with planned study procedures Will provide written informed consent and assent (if age appropriate) prior to initiation of any study procedures Exclusion Criteria: Allergy to eggs or other components of the vaccine, including gelatin, formaldehyde, octoxinol, thimerosal, and chicken protein Positive urine pregnancy test within 24 hours prior to vaccination, if a female of childbearing potential Currently breastfeeding History of smoking 20 pack-years or greater (current or former smokers with a history of less than 20 pack-years can be included in the study) Has been previously diagnosed by a physician with chronic obstructive pulmonary disease, chronic bronchitis, emphysema, or cystic fibrosis Has received anticancer chemotherapy or radiation therapy (cytotoxic) within the past 36 months Has an active neoplastic disease or a history of any hematologic malignancy Has a diagnosis of schizophrenia, bipolar disease, or other major psychiatric diagnosis Has been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others within the past 10 years Receiving psychiatric drugs (subjects who are receiving a single antidepressant drug and are stable for at least 3 months prior to study entry, without de-compensating symptoms, will be allowed to enroll) History of receiving immunoglobulin, including anti-cytokine antibodies, or other blood product within the 3 months prior to vaccination in this study Has received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month prior to vaccination in this study or expect to receive an experimental agent during this study (prior to the Day 141 follow-up call - 100 days after the second vaccination) Has received any live licensed vaccines within 4 weeks or inactivated licensed vaccines within 2 weeks prior to vaccination in this study, or plan receipt of such vaccines within 21 days following the second vaccination Has a history of severe reactions following previous immunization with influenza virus vaccines Has an acute illness, including an oral temperature greater than 100.4°F, within 1 week of either vaccination Has a chronic neurologic or autoimmune disorder Has a history of Guillain-Barré Syndrome Has an acute or chronic medical condition that, in the opinion of the investigator, would render vaccination unsafe, or would interfere with the evaluation of vaccine response Has an ongoing asthma exacerbation or had an asthma exacerbation that was resolved less than 7 days prior to vaccination Has any condition that would, in the opinion of the site investigator, place the participant at an unacceptable risk of injury, render the participant unable to meet the requirements of the protocol, or interfere with the successful completion of the study. Participated in a novel influenza H1N1 2009 vaccine study in the past two years or has a history of novel influenza H1N1 2009 infection or treatment Has known active HIV, Hepatitis B or Hepatitis C infection Has a history of alcohol or drug abuse in the last 5 years Plans to travel outside of North America in the time between the first vaccination and 42 days following the first vaccination Does not speak English primarily

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: H1N1 vaccine high dose<br>Participants will be stratified according to asthma severity and will receive the high dosage of the H1N1 vaccine. | Biological: H1N1 vaccine high dose<br>* 30 mcg of unadjuvanted Novartis H1N1 vaccine delivered as two, 15 micrograms (mcg), intramuscular injections. Each 30 mcg dose is administered 21 days apart.<br>|
| Experimental: H1N1 vaccine low dose<br>Participants will be stratified according to asthma severity and will receive the low dosage of the H1N1 vaccine. | Biological: H1N1 vaccine low dose<br>* 15 mcg of unadjuvanted Novartis H1N1 vaccine delivered in two intramuscular injections 21 days apart<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Serious Adverse Events (SAEs) Attributed To Vaccination | Percentage of participants with serious adverse events (SAEs) attributed to vaccination, as determined by site investigators at the time of reporting. | Measured at Baseline Visit and Days 1, 8, 21, 28, 41, 80, 120, and 201 | 
| Percentage of Participants With Reactogenicity Adverse Events (AEs) Status Post Vaccine 1 | Percentage of participants with reactogenicity AEs, local (erythema, ecchymosis, induration, pain and tenderness at the injection sites) and systemic (feverishness, chills, fatigue, myalgias, arthralgias, headache and nausea), within 8 Days After Vaccination 1 by Dose Level Group. | Days 1 through 8 | 
| Percentage of Participants With Reactogenicity Adverse Events (AEs) Status Post Vaccine 2 | Percentage of participants with reactogenicity AEs, local (erythema, ecchymosis, induration, pain and tenderness at the injection sites) and systemic (feverishness, chills, fatigue, myalgias, arthralgias, headache and nausea), within 8 Days After Vaccination 2 by Dose Level Group. | Days 21 through 28 | 
| Percentage of Participants With Asthma Exacerbations Status Post Vaccine 1 | Percentage of participants with asthma exacerbations within 8 days after vaccination 1. Any of the following events are considered asthma exacerbation: Increase in the daily use of bronchodilator rescue medication for 2 consecutive days; an increase is defined as ≥6puffs of bronchodilator from a metered-dose inhaler or ≥2 uses of nebulized albuterol above average use reported in the two weeks prior to Visit 1. Increase in use of systemic corticosteroids or the addition of systemic corticosteroids to treatment regimen for asthma. Unscheduled use of health care for the treatment of asthma. | Days 1 to 8 | 
| Percentage of Participants With Asthma Exacerbations Status Post Vaccination 2 | Percentage of participants with asthma exacerbations within 8 days after vaccination 2. Any of the following events are considered asthma exacerbation: Increase in the daily use of bronchodilator rescue medication for 2 consecutive days; an increase is defined as ≥6puffs of bronchodilator from a metered-dose inhaler or ≥2 uses of nebulized albuterol above average use reported in the two weeks prior to Visit 1. Increase in use of systemic corticosteroids or the addition of systemic corticosteroids to treatment regimen for asthma. Unscheduled use of health care for the treatment of asthma. | Days 21 to 28 | 
| Percentage of Participants With Seroconversion at Day 28 Following Two Administrations of Vaccination, Mild-Moderate Asthmatics | Seroconversion: The percentage of participants with a four-fold or greater hemagglutination inhibition assay (HAI) antibody titer increase compared to baseline against the novel influenza hemagglutinin type 1 and neuraminidase type 1 (H1N1) 2009 virus following two administrations of Novartis H1N1 vaccine at each dose, combined across age groups. | Days 1 to 28 | 
| Percentage of Participants With Seroconversion at Day 28 Following Two Administrations of Vaccination, Severe Asthmatics | Seroconversion: The percentage of participants with a four-fold or greater hemagglutination inhibition assay (HAI) antibody titer increase compared to baseline against the novel influenza hemagglutinin type 1 and neuraminidase type 1 (H1N1) 2009 virus following two administrations of Novartis H1N1 vaccine at each dose, combined across age groups. | Days 1 to 28 | 
| Percentage of Participants With Seroconversion at Day 41 Following Two Administrations of Vaccination, Mild-Moderate Asthmatics | Seroconversion: The percentage of participants with a four-fold or greater hemagglutination inhibition assay (HAI) antibody titer increase compared to baseline against the novel influenza hemagglutinin type 1 and neuraminidase type 1 (H1N1) 2009 virus following two administrations of Novartis H1N1 vaccine at each dose, combined across age groups. | Days 1 to 41 | 
| Percentage of Participants With Seroconversion at Day 41 Following Two Administrations of Vaccination, Severe Asthmatics | Seroconversion: The percentage of participants with a four-fold or greater hemagglutination inhibition assay (HAI) antibody titer increase compared to baseline against the novel influenza hemagglutinin type 1 and neuraminidase type 1 (H1N1) 2009 virus following two administrations of Novartis H1N1 vaccine at each dose, combined across age groups. | Days 1 to 41 | 
| Percentage of Participants With Seroprotection at Day 28 Following Two Administrations of Vaccination, Mild-Moderate Asthmatics | Seroprotection: The percentage of participants with a hemagglutination inhibition assay (HAI) antibody titer of 1:40 or greater against influenza H1N1 2009 virus following two administrations of the H1N1 vaccine at each dose, combined across age groups. | Days 1 to 28 | 
| Percentage of Participants With Seroprotection at Day 28 Following Two Administrations of Vaccination, Severe Asthmatics | Percentage of participants with seroprotection defined as a hemagglutination inhibition assay (HAI) antibody titer of 1:40 or greater against influenza H1N1 2009 virus following two administrations of the H1N1 vaccine at each dose, combined across age groups. | Days 1 to 28 | 
| Percentage of Participants With Seroprotection at Day 41 Following Two Administrations of Vaccination, Mild-Moderate Asthmatics | Percentage of participants with seroprotection defined as a hemagglutination inhibition assay (HAI) antibody titer of 1:40 or greater against influenza H1N1 2009 virus following two administrations of the H1N1 vaccine at each dose, combined across age groups. | Days 1 to 41 | 
| Percentage of Participants With Seroprotection at Day 41 Following Two Administrations of Vaccination, Severe Asthmatics | Percentage of participants with seroprotection defined as a hemagglutination inhibition assay (HAI) antibody titer of 1:40 or greater against influenza H1N1 2009 virus following two administrations of the H1N1 vaccine at each dose, combined across age groups. | Days 1 to 41 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Seroconversion at Day 21 Following Single Administration of Vaccination, Mild-Moderate Asthmatics | Percentage of participants with seroconversion defined as a four-fold or greater hemagglutination inhibition assay (HAI) antibody titer increase compared to baseline against the novel influenza hemagglutinin type 1 and neuraminidase type 1 (H1N1) 2009 virus following a single administration of Novartis H1N1 vaccine at each dose, combined across age groups. | Days 1 to 21 | 
| Percentage of Participants With Seroconversion at Day 21 Following Single Administration of Vaccination, Severe Asthmatics | Percentage of participants with seroconversion defined as a four-fold or greater hemagglutination inhibition assay(HAI) antibody titer increase compared to baseline against the novel influenza hemagglutinin type 1 and neuraminidase type 1 (H1N1) 2009 virus following a single administration of Novartis H1N1 vaccine at each dose, combined across age groups. | Days 1 to 21 | 
| Percentage of Participants With Seroprotection at Day 21 Following Single Administration of Vaccination, Mild-Moderate Asthmatics | Percentage of participants with seroprotection defined as hemagglutination inhibition assay (HAI) antibody titer of 1:40 or greater against influenza H1N1 2009 virus following a single administration of the H1N1 vaccine at each dose, combined across age groups. | Days 1 to 21 | 
| Percentage of Participants With Seroprotection at Day 21 Following Single Administration of Vaccination, Severe Asthmatics | Percentage of participants with seroprotection defined as hemagglutination inhibition assay (HAI) antibody titer of 1:40 or greater against influenza H1N1 2009 virus following a single administration of the H1N1 vaccine at each dose, combined across age groups. | Days 1 to 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza A Virus, H1N1 Subtype, Vaccine