Safety Study to Evaluate FluMist in Immunocompromised Children

Study Overview
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Brief Summary
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The main purpose of this study is to get information about the safety of a flu vaccine spray, called FluMist, in children with cancer. The study is also being done to find out how much and how long the vaccine spray can be found in the nose.

Detailed Description
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This study is a randomized, double-blind Phase 1 study of FluMist vs. placebo in mild to moderately immunocompromised children 5 to 17 years of age with cancer. The primary objective of this study is to describe the safety of FluMist compared with placebo in mild to moderately immunocompromised children with cancer. The secondary objectives of this study are to describe the immune responses following vaccination with FluMist and to determine the incidence and duration of viral replication following vaccination with FluMist. The standard 0.5 mL dose of vaccine or placebo was administered intranasally. Patients were evaluated at four visits scheduled between days 3-5, days 7-10, days 14-28, and days 35-42 for viral shedding via nasal swabs. Safety outcomes were collected at study clinic visits or by telephone contact through 42 days post dose. Serious adverse events and significant new medical conditions were collected through 180 days after receipt of investigational product. Immune responses were measured by detection of influenza-specific antibodies as measured by the standard hemagglutination inhibition (HAI) assay. Influenza-specific serum antibody isotype levels were determined and nasal swab specimens were analyzed for the expression of influenza-specific immunoglobulin A (IgA). Serum was analyzed for its ability to neutralize viral particles from infecting Madin-Darby canine kidney cells (microneutralization). Baseline immunosuppression as measured by expression of T- and B-lymphocyte subsets was compared to immunosuppression at time points after vaccination. The duration of viral replication and the titers of live-attenuated influenza virus shed was evaluated from nasal swab specimens collected at scheduled time points after administration of FluMist.

Official Title
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A Phase I Randomized, Double-Blind Trial of the Safety and Immunogenicity of FluMist® A Live, Intranasal Influenza Virus Vaccine vs. Placebo in Immunocompromised Children Ages 5 Through 17 Years of Age

Conditions
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Cancer

Intervention / Treatment
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* Biological: FluMist
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 5 through 17 years of age (not yet reached their 18th birthday) at the time of entry into the study; Patient's parent or legal guardian available by telephone during the course of the study; Written informed consent (assent if applicable) and Health Insurance Portability and Accountability Act (HIPAA) authorization (if applicable) obtained from the patient's parent or legal guardian; Ability of the patient or patient's parent/guardian to comply with the requirements of the protocol; Currently receiving chemotherapy and/or radiation therapy for the treatment of cancer or have received chemotherapy in the past 12 weeks; If the subject's underlying cancer is a solid tumor, current status must be stable disease, partial response, or complete response to therapy; if the subject's underlying disease is a hematologic malignancy, current status must be in remission; Estimated life expectancy of >1 year; and Currently has no worse than mild to moderate immunosuppression (meets none of the exclusion criteria). Exclusion Criteria: History of hypersensitivity to any component of FluMist, including egg or egg products, or monosodium glutamate; History of hypersensitivity to gentamicin; Close contact with a severely immunocompromised patient (e.g., a hematopoietic stem cell transplant patient, during those periods in which the immunocompromised patient requires care in a protective environment); History of Guillain-Barré syndrome; History of asthma; Use of aspirin or salicylate-containing products in the 30 days prior to study vaccination or expected receipt within the study duration; Use of anti-influenza medications (including amantadine, rimantadine, oseltamivir, and zanamivir) within 14 days prior to enrollment or expected receipt (unless medically indicated) during this study; Currently receiving inhaled steroid therapy; Receipt of immunoglobulin within the past 90 days; Receipt of stem cell transplant; Acute febrile [>100.0°F (37.8°C) oral] illness or acute respiratory illness, e.g., cough or sore throat, within three days prior to enrollment; Administration of any live vaccine within 30 days prior to enrollment or if receipt of another live vaccine is expected within 30 days after the vaccination in this study; Administration of any inactivated vaccine within two weeks prior to enrollment or if receipt of another inactivated vaccine is expected within two weeks after the vaccination in this study; Receipt of an investigational product studied under an investigational new drug (IND) within 10 days prior to study entry or expected receipt of such an investigational product within 10 days after study vaccination (Note: an investigational product not studied under an IND is allowed at the investigator's discretion); Pregnancy or, in biologically capable females (e.g., menses within the last year), not willing to agree to acceptable birth control for three months after study vaccination (for those biologically capable, a urine pregnancy test must be performed on the day of vaccination with a negative result); Female who is breastfeeding or lactating; Any condition or receipt of other medication that, in the opinion of the investigator, might interfere with the evaluation of the vaccine or interpretation of study results; At the study screening visit (within 16 days before study vaccination) a CD4+ T cell percentage of <15%; At study entry, an absolute neutrophil count less than or equal to 500 cells/mm3; Receipt of high-dose systemic corticosteroids (≥ 2 mg/kg total of prednisone or equivalent given daily or on alternating days) for ≥ 14 consecutive days within 30 days prior to or following study vaccination

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FluMist<br>The total volume of 0.5 mL was administered intranasally with a spray applicator (approximately 0.25 mL into each nostril). Each dose contained approximately 10 to 7th TCID 50 (median tissue culture infectious dose) of each of three influenza virus strains. During the 2005 enrollment period, the three 2004/2005 influenza virus strains were used: A/New Caledonia/20/99(H1N1), A/Wyoming/03/2003(H3N2), and B/Jilin/20/2003). During the 2006 and 2007 enrollment periods, the three 2005/2006 influenza virus strains were used: A/New Caledonia/20/99(H1N1), A/California/7/2004(H3N2), and B/Jiangsu/10/2003 (B/Shanghai/361/2002-like. | Biological: FluMist<br>* The total volume of 0.5 mL was administered intranasally with a spray applicator (approximately 0.25 mL into each nostril). Each dose contained approximately 10 to 7th TCID 50 (median tissue culture infectious dose) of each of three influenza virus strains. During the 2005 enrollment period, the three 2004/2005 influenza virus strains were used: A/New Caledonia/20/99(H1N1), A/Wyoming/03/2003(H3N2), and B/Jilin/20/2003). During the 2006 and 2007 enrollment periods, the three 2005/2006 influenza virus strains were used: A/New Caledonia/20/99(H1N1), A/California/7/2004(H3N2), and B/Jiangsu/10/2003 (B/Shanghai/361/2002-like. brief description of the arm. This element may not be necessary if the associated intervention descriptions contain sufficient information to describe the arm.<br>|
| Placebo Comparator: Placebo<br>Placebo intranasal mist was composed of allantoic fluid stabilized with buffer containing sucrose, potassium phosphate, and monosodium glutamate. The total volume of 0.5 mL was administered intranasally with a spray applicator (approximately 0.25 mL into each nostril). | Biological: Placebo<br>* Placebo intranasal mist was composed of allantoic fluid stabilized with buffer containing sucrose, potassium phosphate, and monosodium glutamate. The total volume of 0.5 mL was administered intranasally with a spray applicator (approximately 0.25 mL into each nostril).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Had Reactogenicity Events (REs) | Reactogenicity events (REs) are predefined solicited adverse events (AEs) that can potentially occur after vaccine administration. The REs for this study included fever, runny nose/nasal congestion, sore throat, cough, vomiting, headache, muscle aches, chills, tiredness, and irritability. | 0-42 days after study vaccination | 
| Number of Participants Who Had Serious Adverse Events (SAEs) | An SAE is any AE that results in any of the following outcomes: •Death • Life-threatening • Inpatient hospitalization or prolongation of existing hospitalization • Persistent or significant disability or incapacity • Congenital anomaly/birth defect (in the offspring of a study participant) • An important medical event that may may jeopardize the study participant and may require medical or surgical intervention to prevent one of the outcomes listed above. | 0-180 days after study vaccination | 
| Number of Participants Who Had Adverse Events (AEs) | An AE is any untoward medical occurrence in a patient or clinical investigations study participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | 0-42 days after study vaccination | 
| Number of Significant New Medical Conditions (SNMCs) | A significant new medical condition is defined as a new diagnosis of a chronic medical condition that does not meet the criteria of a SAE. | 43-180 days after study vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Shedding Vaccine-like Virus | Number of participants with nasal swab samples that contained vaccine-like virus are reported. | 3-5 days after study vaccination | 
| Number of Participants Shedding Vaccine-like Virus | Number of participants with nasal swab samples that contained vaccine-like virus are reported. | 7-10 days after study vaccination | 
| Number of Participants Shedding Vaccine-like Virus | Number of participants with nasal swab samples that contained vaccine-like virus are reported. | 14-28 days after study vaccination | 
| Number of Participants Shedding Vaccine-like Virus | Number of participants with nasal swab samples that contained vaccine-like virus are reported. Sample was collected at this time point only if health assessment indicated presence of a respiratory illness, including otitis media. | 35-42 days after study vaccination | 
| Number of Participants Shedding Vaccine-like Virus | Number of participants with nasal swab samples that contained vaccine-like virus are reported. | Unscheduled visits occurring during 0-42 days after study vaccination | 
| T- and B-lymphocyte Subsets by Flow Cytometry - Cluster of Differentiation (CD) 19 | Mean and standard deviation results of CD19 lymphocyte subsets as a percentage of total lymphocytes. | pre-dosing (Day 0) | 
| T- and B-lymphocyte Subsets by Flow Cytometry - CD3 | Mean and standard deviation results of CD3 lymphocyte subsets as a percentage of total lymphocytes. | pre-dosing (Day 0) | 
| T- and B-lymphocyte Subsets by Flow Cytometry - CD4 | Mean and standard deviation results of CD4 lymphocyte subsets as a percentage of total lymphocytes. | pre-dosing (Day 0) | 
| T- and B-lymphocyte Subsets by Flow Cytometry - CD8 | Mean and standard deviation results of CD8 lymphocyte subsets as a percentage of total lymphocytes. | pre-dosing (Day 0) | 
| T- and B-lymphocyte Subsets by Flow Cytometry - CD19 | Mean and standard deviation results of CD19 lymphocyte subsets as a percentage of total lymphocytes. | 7-10 days after study vaccination | 
| T- and B-lymphocyte Subsets by Flow Cytometry - CD3 | Mean and standard deviation results of CD3 lymphocyte subsets as a percentage of total lymphocytes. | 7-10 days after study vaccination | 
| T- and B-lymphocyte Subsets by Flow Cytometry - CD4 | Mean and standard deviation results of CD4 lymphocyte subsets as a percentage of total lymphocytes. | 7-10 days after study vaccination | 
| T- and B-lymphocyte Subsets by Flow Cytometry - CD8 | Mean and standard deviation results of CD8 lymphocyte subsets as a percentage of total lymphocytes. | 7-10 days after study vaccination | 
| Interferon (INF)-Gamma | Mean and standard deviation spots-forming cells per 10^5 T cells is reported. | pre-dosing (Day 0) | 
| INF-Gamma | Mean and standard deviation spots-forming cells per 10^5 T cells is reported. | 7-10 days after study vaccination | 
| INF-Gamma | Mean and standard deviation spots-forming cells per 10^5 T cells is reported. | 35-42 days after study vaccination | 
| Interleukin (IL)-4 | Mean and standard deviation spots-forming cells per 10^5 T cells is reported. | pre-dosing (Day 0) | 
| IL-4 | Mean and standard deviation spots-forming cells per 10^5 T cells is reported. | 7-10 days after study vaccination | 
| IL-4 | Mean and standard deviation spots-forming cells per 10^5 T cells is reported. | 35-42 days after study vaccination | 
| Human Leukocyte Antigen (HLA) Matched Tetramers CD8+ | The antigen-specific response of the T cell populations was measured using HLA-matched tetramers specific for human CD8 cell populations. | pre-dosing (Day 0) | 
| HLA Matched Tetramers CD8+ | The antigen-specific response of the T cell populations was measured using HLA-matched tetramers specific for human CD8 cell populations. | 7-10 days after study vaccination | 
| HLA Matched Tetramers CD8+ | The antigen-specific response of the T cell populations was measured using HLA-matched tetramers specific for human CD8 cell populations. | 35-42 days after study vaccination | 
| Number of Participants Who Experienced a >= 4-fold Rise in Serum Influenza A/H1N1 Hemagglutination Inhibition (HAI) Titers From Baseline to Day 35-42 | Participants with a geometric mean fold-rise in influenza-specific nasal HAI titers >= 4 from baseline are reported. | Baseline (pre-dosing on Day 0) and 35-42 days after study vaccination | 
| Number of Participants Who Experienced a >= 4-fold Rise in Serum Influenza A/H3N2 HAI Titers From Baseline to Day 35-42 | Participants with a geometric mean fold-rise in influenza-specific nasal HAI titers >= 4 from baseline are reported. | Baseline (pre-dosing on Day 0) and 35-42 days after study vaccination | 
| Number of Participants Who Experienced a >= 4-fold Rise in Serum Influenza B HAI Titers From Baseline to Day 35-42 | Participants with a geometric mean fold-rise in influenza-specific nasal HAI titers >= 4 from baseline are reported. | Baseline (pre-dosing on Day 0) and 35-42 days after study vaccination | 
| Number of Participants Who Experienced a >= 4-fold Rise in Influenza A/H1N1 Microneutralization Titers From Baseline to Day 35-42 | Participants with a geometric mean fold-rise in influenza-specific nasal microneutralization titers >= 4 from baseline are reported. | Baseline (pre-dosing on Day 0) and 35-42 days after study vaccination | 
| Number of Participants Who Experienced a >= 4-fold Rise in Influenza A/H3N2 Microneutralization Titers From Baseline to Day 35-42 | Participants with a geometric mean fold-rise in influenza-specific nasal microneutralization titers >= 4 from baseline are reported. | Baseline (pre-dosing on Day 0) and 35-42 days after study vaccination | 
| Number of Participants Who Experienced a >= 4-fold Rise in Influenza B Microneutralization Titers From Baseline to Day 35-42 | Participants with a geometric mean fold-rise in influenza-specific nasal microneutralization titers >= 4 from baseline are reported. | Baseline (pre-dosing on Day 0) and 35-42 days after study vaccination | 
| Influenza A/H1N1 Immunoglobulin A (IgA) | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | pre-dosing (Day 0) | 
| Influenza A/H1N1 IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 3-5 days after study vaccination | 
| Influenza A/H1N1 IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 7-10 days after study vaccination | 
| Influenza A/H1N1 IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 14-28 days after study vaccination | 
| Influenza A/H1N1 IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 35-42 days after study vaccination | 
| Influenza A/H3N2 IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | pre-dosing (Day 0) | 
| Influenza A/H3N2 IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 3-5 days after study vaccination | 
| Influenza A/H3N2 IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 7-10 days after study vaccination | 
| Influenza A/H3N2 IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 14-28 days after study vaccination | 
| Influenza A/H3N2 IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 35-42 days after study vaccination | 
| Influenza B IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | pre-dosing (Day 0) | 
| Influenza B IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 3-5 days after study vaccination | 
| Influenza B IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 7-10 days after study vaccination | 
| Influenza B IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 14-28 days after study vaccination | 
| Influenza B IgA | Mean of influenza-specific IgA from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 35-42 days after study vaccination | 
| T- and B-lymphocyte Subsets by Flow Cytometry - CD56 | Mean and standard deviation results of CD56 lymphocyte subsets is reported. | pre-dosing (Day 0) | 
| T- and B-lymphocyte Subsets by Flow Cytometry - CD56 | Mean and standard deviation results of CD56 lymphocyte subsets is reported. | 7-10 days after study vaccination | 
| T- and B-lymphocyte Subsets by Flow Cytometry - White Blood Cells | Mean and standard deviation results of white blood cells subsets is reported. | pre-dosing (Day 0) | 
| T- and B-lymphocyte Subsets by Flow Cytometry - White Blood Cells | Mean and standard deviation results of white blood cells subsets is reported. | 7-10 days after study vaccination | 
| T- and B-lymphocyte Subsets by Flow Cytometry - Lymphocytes | Mean and standard deviation results of lymphocytes subsets is reported. | pre-dosing (Day 0) | 
| T- and B-lymphocyte Subsets by Flow Cytometry - Lymphocytes | Mean and standard deviation results of lymphocytes subsets is reported. | 7-10 days after study vaccination | 
| T- and B-lymphocyte Subsets by Flow Cytometry - Absolute Lymphocytes | Mean and standard deviation results of absolute lymphocytes subsets is reported. | pre-dosing (Day 0) | 
| T- and B-lymphocyte Subsets by Flow Cytometry - Absolute Lymphocytes | Mean and standard deviation results of absolute lymphocytes subsets is reported. | 7-10 days after study vaccination | 
| T- and B-lymphocyte Subsets by Flow Cytometry - Absolute Neutrophils | Mean and standard deviation results of absolute neutrophils subsets is reported. | pre-dosing (Day 0) | 
| Influenza A/H1N1 Immunoglobulin G (IgG) | Mean of influenza-specific IgG from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | pre-dosing (Day 0) | 
| Influenza A/H1N1 IgG | Mean of influenza-specific IgG from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 35-42 days after study vaccination | 
| Influenza A/H3N2 IgG | Mean of influenza-specific IgG from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | pre-dosing (Day 0) | 
| Influenza A/H3N2 IgG | Mean of influenza-specific IgG from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 35-42 days after study vaccination | 
| Influenza B IgG | Mean of influenza-specific IgG from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | pre-dosing (Day 0) | 
| Influenza B IgG | Mean of influenza-specific IgG from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 35-42 days after study vaccination | 
| Influenza A/H1N1 Immunoglobulin M (IgM) | Mean of influenza-specific IgM from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | pre-dosing (Day 0) | 
| Influenza A/H1N1 IgM | Mean of influenza-specific IgM from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 35-42 days after study vaccination | 
| Influenza A/H3N2 IgM | Mean of influenza-specific IgM from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | pre-dosing (Day 0) | 
| Influenza A/H3N2 IgM | Mean of influenza-specific IgM from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 35-42 days after study vaccination | 
| Influenza B IgM | Mean of influenza-specific IgM from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | pre-dosing (Day 0) | 
| Influenza B IgM | Mean of influenza-specific IgM from nasal swab is reported. Titers of < 1 were assigned the value of 0.5. | 35-42 days after study vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, pediatric, influenza, vaccine