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Children are particularly vulnerable to respiratory virus infections, especially influenza. Vitamin A & D deficiencies are associated with vulnerability to infectious diseases of the respiratory tract. The central hypothesis of this protocol is that vitamin supplements will enhance antibody responses toward the flu vaccine in children. Children, 2-8 years old, will be randomized to receive influenza virus vaccine with a vitamin A+D supplement or influenza virus vaccine with placebo. Children will be tested for vitamin levels and immune responses before and after influenza virus vaccinations to determine if vitamin supplementation improves the influenza virus vaccine-induced immune response.
PRIMARY OBJECTIVE:
SECONDARY OBJECTIVE:
Participants will be randomized to receive either an influenza virus vaccine plus Vitamins A & D or an influenza virus vaccine plus placebo. They will be stratified based on retinol binding protein (RBP) levels at screening, using a cut-off indicative of Vitamin A insufficiency (≤22,000 ng/ml). Co-enrolled sibling participants will be first stratified by RBP levels, then siblings within the same stratum will be equally assigned to different arms to provide greater assurance of balanced treatment assignment. Children will be tested for vitamin levels and immune responses before and after influenza virus vaccinations to determine if vitamin supplementation improves the influenza virus vaccine-induced antibody immune response.
All participants will receive two doses of an influenza virus vaccination administered at least 28 days apart. Vitamin levels and antibody responses toward the vaccine will be measured on day 0 (baseline levels obtained where day 0 equals the first influenza virus vaccination administration), day 28, and day 56. Placebo or Vitamins A + D (at the levels of 20,000 IU and 2,000 IU, respectively) will be administered orally on the days of vaccination.
Blood serum samples will be collected from participants on Day 0, prior to receiving influenza virus vaccine on Day 28, and during their Day 56 follow-up visit.
Parents will be asked to fill out diary cards to indicate food intake for children during the study period along with an optional food frequency questionnaire given on day 56. Specific measurements on days 28, and 56 will include analyses of vaccine-specific and total IgA, IgG, and IgA/IgG plus IgA/IgM ratios in sera. Functional activities of antibodies toward influenza vaccine will also be measured.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Influenza Virus Vaccine Plus Vitamins A and D | Active Comparator | Participants receive influenza virus vaccine and Vitamins A and D supplement on Day 0 and Day 28. |
|
| Influenza Virus Vaccine Plus Placebo | Placebo Comparator | Participants receive influenza virus vaccine and matched placebo on Day 0 and Day 28. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Influenza virus vaccine | Biological | Children will have the first influenza virus vaccine dose (dose 1) administered on day 0 of the trial, and the second dose (dose 2) administered 28 days later. |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With Positive Responses in Virus-specific Antibody in Sera | The percentage of 2X increases or conversion from undetectable to detectable response in virus-specific antibody toward any vaccine component after 2 immunizations in intervention and control groups will be reported. | Day 56 after vaccination |
| Isotype Ratios on Day 56 | Isotype ratios will be summarized with descriptive statistics. | Day 56 after vaccination |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With Seroconversion at Day 56 After Vaccination, Overall | Secondary analyses will examine sero-conversion based on antibody functions (HAI or neutralization) defined as antibody titers of <1:40 converting to ≥1:40, or a four-fold increase in titer for participants with a starting titer of ≥1:40. Sero-conversion rate (expressed as percentage) will be estimated with 95% confidence interval. The rate difference will be described with point estimate and 95% confidence interval. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nehali Patel, MD | St. Jude Children's Research Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St. Jude Children's Research Hospital | Memphis | Tennessee | 38105 | United States |
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| Label | URL |
|---|---|
| St. Jude Children's Research Hospital | View source |
| Clinical Trials Open at St. Jude | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | A&D - S1 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2015-16 season |
| FG001 | Placebo - S1 | Participants receiving influenza virus vaccine plus matched placebo in 2015-16 season |
| FG002 | A&D - S2 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2016-17 season |
| FG003 | Placebo - S2 | Participants receiving influenza virus vaccine plus matched placebo in 2016-17 season |
| FG004 | A&D - S3 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2017-18 season |
| FG005 | Placebo - S3 | Participants receiving influenza virus vaccine plus matched placebo in 2017-18 season |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | A&D-S1 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2015-16 season |
| BG001 | Placebo - S1 | Participants receiving influenza virus vaccine plus matched placebo in 2015-16 season |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Participants With Positive Responses in Virus-specific Antibody in Sera | The percentage of 2X increases or conversion from undetectable to detectable response in virus-specific antibody toward any vaccine component after 2 immunizations in intervention and control groups will be reported. | All enrolled subjects who satisfied the inclusion/exclusion criteria were included in the analysis. For the four participants who didn't complete the study, results after one immunization were used. | Posted | Number | percentage of participants | Day 56 after vaccination |
|
56 days after the final participant was dosed on Day 0.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | A&D-S1 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2015-16 season |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Allergic rhinitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Nehali Patel, MD | St. Jude Children's Research Hospital | 866-278-5833 | info@stjude.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 14, 2018 | Jun 25, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D007251 | Influenza, Human |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D009976 | Orthomyxoviridae Infections |
| D012327 | RNA Virus Infections |
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| ID | Term |
|---|---|
| D007252 | Influenza Vaccines |
| C007792 | Fumigant 93 |
| D019587 | Dietary Supplements |
| D008508 | Medication Errors |
| ID | Term |
|---|---|
| D014765 | Viral Vaccines |
| D014612 | Vaccines |
| D001688 | Biological Products |
| D045424 | Complex Mixtures |
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|
| Vitamins A and D | Dietary Supplement | The chewable gummy contains either Vitamin A (20,000 International Units) and Vitamin D3 (2,000 International Units), which should be fully chewed under supervision of study staff with documentation in the participant's research record and eMAR (electronic medical administration record). The chewable gummy should be administered prior to receiving influenza virus vaccination. |
|
|
| Placebo | Other | The chewable gummy matched placebo will be formulated with gelatin base and tangerine oil and match the Vitamin A and D in shape, taste, texture, and appearance. Gummies should be fully chewed under supervision of study staff with documentation in the participant's research record and eMAR (electronic medical administration record). The chewable gummy should be administered prior to receiving influenza virus vaccination. |
|
|
| Day 56 after vaccination |
| Percentage of Participants With Seroconversion at Day 56 After Vaccination, by Vitamin A Levels at Screening | Secondary analyses will examine sero-conversion based on antibody functions (HAI or neutralization) defined as antibody titers of <1:40 converting to ≥1:40, or a four-fold increase in titer for participants with a starting titer of ≥1:40. Sero-conversion rate (expressed as percentage) will be estimated with 95% confidence interval for participants sufficient and insufficient in vitamin A at screening. | Day 56 after vaccination |
| HAI Titers at Day 56 After Vaccination, Overall | Day 56 after vaccination |
| HAI Titers at Day 56 After Vaccination, by Vitamin A Levels at Screening | Day 56 after vaccination |
| BG002 | A&D - S2 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2016-17 season |
| BG003 | Placebo - S2 | Participants receiving influenza virus vaccine plus matched placebo in 2016-17 season |
| BG004 | A&D - S3 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2017-18 season |
| BG005 | Placebo - S3 | Participants receiving influenza virus vaccine plus matched placebo in 2017-18 season |
| BG006 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
Participants receiving influenza virus vaccine plus matched placebo in 2015-16 season |
| OG002 | A&D - S2 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2016-17 season |
| OG003 | Placebo - S2 | Participants receiving influenza virus vaccine plus matched placebo in 2016-17 season |
| OG004 | A&D - S3 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2017-18 season |
| OG005 | Placebo - S3 | Participants receiving influenza virus vaccine plus matched placebo in 2017-18 season |
|
|
| Primary | Isotype Ratios on Day 56 | Isotype ratios will be summarized with descriptive statistics. | Subjects with complete isotype data at day 56. Subjects with an undetermined assay result were not included in analyses. In some cases, the limit of detection (LOD) for the assay was reached and that LOD value was used in calculations. | Posted | Median | Full Range | ratio | Day 56 after vaccination |
|
|
|
|
| Secondary | Percentage of Participants With Seroconversion at Day 56 After Vaccination, Overall | Secondary analyses will examine sero-conversion based on antibody functions (HAI or neutralization) defined as antibody titers of <1:40 converting to ≥1:40, or a four-fold increase in titer for participants with a starting titer of ≥1:40. Sero-conversion rate (expressed as percentage) will be estimated with 95% confidence interval. The rate difference will be described with point estimate and 95% confidence interval. | Subjects with complete HAI data at day 56. Subjects without a day 56 sample were not included in analyses. | Posted | Number | 95% Confidence Interval | percentage of participants | Day 56 after vaccination |
|
|
|
|
| Secondary | Percentage of Participants With Seroconversion at Day 56 After Vaccination, by Vitamin A Levels at Screening | Secondary analyses will examine sero-conversion based on antibody functions (HAI or neutralization) defined as antibody titers of <1:40 converting to ≥1:40, or a four-fold increase in titer for participants with a starting titer of ≥1:40. Sero-conversion rate (expressed as percentage) will be estimated with 95% confidence interval for participants sufficient and insufficient in vitamin A at screening. | Subjects with complete HAI data at day 56. Subjects without a day 56 sample were not included in analyses. | Posted | Number | 95% Confidence Interval | percentage of participants | Day 56 after vaccination |
|
|
|
| Secondary | HAI Titers at Day 56 After Vaccination, Overall | Subjects with complete HAI data at day 56. Subjects without a day 56 sample were not included in analyses. | Posted | Median | Full Range | titers | Day 56 after vaccination |
|
|
|
| Secondary | HAI Titers at Day 56 After Vaccination, by Vitamin A Levels at Screening | Subjects with complete HAI data at day 56. Subjects without a day 56 sample were not included in analyses. | Posted | Median | Full Range | titers | Day 56 after vaccination |
|
|
|
| 0 |
| 5 |
| 0 |
| 5 |
| 5 |
| 5 |
| EG001 | Placebo - S1 | Participants receiving influenza virus vaccine plus matched placebo in 2015-16 season | 0 | 4 | 0 | 4 | 2 | 4 |
| EG002 | A&D - S2 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2016-17 season | 0 | 22 | 0 | 22 | 6 | 22 |
| EG003 | Placebo - S2 | Participants receiving influenza virus vaccine plus matched placebo in 2016-17 season | 0 | 22 | 0 | 22 | 6 | 22 |
| EG004 | A&D - S3 | Participants receiving influenza virus vaccine plus vitamin A and D supplements in 2017-18 season | 0 | 12 | 0 | 12 | 4 | 12 |
| EG005 | Placebo - S3 | Participants receiving influenza virus vaccine plus matched placebo in 2017-18 season | 0 | 14 | 0 | 14 | 3 | 14 |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Rhinorrhea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Sneezing | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Streptococcal | Infections and infestations | Systematic Assessment |
|
| Upper respiratory infection | Infections and infestations | Systematic Assessment |
|
| Fever | Infections and infestations | Systematic Assessment |
|
| Facial trauma/fractured | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Left forearm bruise | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
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| D014777 | Virus Diseases |
| D012140 | Respiratory Tract Diseases |
| D005502 |
| Food |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |
| D019602 | Food and Beverages |
| D004358 | Drug Therapy |
| D013812 | Therapeutics |
| D019300 | Medical Errors |
| D006296 | Health Services |
| D005159 | Health Care Facilities Workforce and Services |
| IgA/IgG2 |
|
| IgA/IgG3 |
|
| IgA/IgM |
|
| Wilcoxon (Mann-Whitney) |
| 0.49 |
| Superiority |
| Null hypothesis: No difference between intervention and placebo groups in the ratio of IgA/IgG1 at day 56 in 2017-18 season | Wilcoxon (Mann-Whitney) | 0.50 | Superiority |
| Null hypothesis: No difference between intervention and placebo groups in the ratio of IgA/IgG2 at day 56 in 2015-16 season | Wilcoxon (Mann-Whitney) | 0.90 | Superiority |
| Null hypothesis: No difference between intervention and placebo groups in the ratio of IgA/IgG2 at day 56 in 2016-17 season | Wilcoxon (Mann-Whitney) | 0.76 | Superiority |
| Null hypothesis: No difference between intervention and placebo groups in the ratio of IgA/IgG2 at day 56 in 2017-18 season | Wilcoxon (Mann-Whitney) | 0.65 | Superiority |
| Null hypothesis: No difference between intervention and placebo groups in the ratio of IgA/IgG3 at day 56 in 2015-16 season | Wilcoxon (Mann-Whitney) | 0.90 | Superiority |
| Null hypothesis: No difference between intervention and placebo groups in the ratio of IgA/IgG3 at day 56 in 2016-17 season | Wilcoxon (Mann-Whitney) | 0.76 | Superiority |
| Null hypothesis: No difference between intervention and placebo groups in the ratio of IgA/IgG3 at day 56 in 2017-18 season | Wilcoxon (Mann-Whitney) | 0.54 | Superiority |
| Null hypothesis: No difference between intervention and placebo groups in the ratio of IgA/IgM at day 56 in 2015-16 season | Wilcoxon (Mann-Whitney) | 0.90 | Superiority |
| Null hypothesis: No difference between intervention and placebo groups in the ratio of IgA/IgM at day 56 in 2016-17 season | Wilcoxon (Mann-Whitney) | 0.95 | Superiority |
| Null hypothesis: No difference between intervention and placebo groups in the ratio of IgA/IgM at day 56 in 2017-18 season | Wilcoxon (Mann-Whitney) | 0.34 | Superiority |
| H3N2 |
|
| B/Phuket |
|
| B/Brisbane |
|
| Treatment Difference in Seroconversion R |
| -23.6 |
| 2-Sided |
| 95 |
| -51.7 |
| 6.2 |
Treatment group minus placebo |
| Superiority |
| H1N1 | Treatment Difference in Seroconversion R | -13.0 | 2-Sided | 95 | -49.4 | 26.5 | Treatment group minus placebo | Superiority |
| H3N2 | Treatment Difference in Seroconversion R | -10.0 | 2-Sided | 95 | -70.1 | 56.1 | Treatment group minus placebo | Superiority |
| H3N2 | Treatment Difference in Seroconversion R | -8.6 | 2-Sided | 95 | -38.8 | 20.6 | Treatment group minus placebo | Superiority |
| H3N2 | Treatment Difference in Seroconversion R | 22.7 | 2-Sided | 95 | -17.5 | 57.9 | Treatment group minus placebo | Superiority |
| B/Phuket | Treatment Difference in Seroconversion R | 0 | 2-Sided | 95 | 0 | 0 | Treatment group minus placebo | Superiority |
| B/Phuket | Treatment Difference in Seroconversion R | -26.4 | 2-Sided | 95 | -54.1 | 5.8 | Treatment group minus placebo | Superiority |
| B/Phuket | Treatment Difference in Seroconversion R | 16.9 | 2-Sided | 95 | -23.1 | 53.3 | Treatment group minus placebo | Superiority |
| B/Brisbane | Treatment Difference in Seroconversion R | 0 | 2-Sided | 95 | 0 | 0 | Treatment group minus placebo | Superiority |
| B/Brisbane | Treatment Difference in Seroconversion R | -26.4 | 2-Sided | 95 | -54.1 | 5.8 | Treatment group minus placebo | Superiority |
| B/Brisbane | Treatment Difference in Seroconversion R | -8.4 | 2-Sided | 95 | -45.4 | 30.5 | Treatment group minus placebo | Superiority |
| H3N2 |
|
| B/Phuket |
|
| B/Brisbane |
|
| H3N2 |
|
| B/Phuket |
|
| B/Brisbane |
|
| H3N2 |
|
| B/Phuket |
|
| B/Brisbane |
|