A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Safety of MEDI-559 in Healthy 1 to <24 Month-Old Children

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to describe the 28-day post-final dose safety and tolerability of three doses of MEDI-559 at 10^5 FFU when administered to healthy RSV seronegative children 1 to <24 months of age.

Detailed Description
-----------------
This is a randomized, double-blind, placebo-controlled, multi-dose, Phase 1/2a multi-center trial to evaluate the safety, tolerability, viral shedding, immunogenicity, and genotypic and phenotypic stability of MEDI-559 in RSV seronegative infants 5 to <24 months of age and in infants 1 to <3 months of age regardless of baseline serostatus. The primary objective of this study is to describe the 28-day post-final dose safety and tolerability of three doses of MEDI-559 at 10^5 FFU when administered to healthy RSV seronegative children 5 to <24 months of age and to healthy infants 1 to <3 months of age regardless of baseline serostatus. MEDI-559 will be administered at a dose of 10^5 fluorescent focus units (FFU) on a 0, 2, and 4 month schedule to two cohorts of subjects in a step-wise fashion. The target sample size for this study is 320 subjects, with 160 subjects 5 to <24 months of age enrolled into Cohort 1 and 160 subjects 1 to <3 months of age enrolled into Cohort 2. Each cohort will be randomized 1:1 (MEDI-559 to placebo) and stratified by site. Cohort 1 will initiate dosing at 10^5 FFU MEDI-559. Blinded safety data from the first 40 subjects enrolled in Cohort 1 for the 28 days following administration of the first dose of vaccine will be reviewed. If no safety concerns are noted, Cohort 2 will initiate dosing at 10^5 FFU. Enrollment into Cohort 2 will be halted after approximately 40 subjects have been randomized, and blinded safety data will be reviewed through 28 days post Dose 1. If no safety concerns are noted, the remainder of Cohort 2 will be enrolled. All subjects will be followed through 365 days after randomization to ensure that each subject has been followed through an RSV season.

Official Title
-----------------
A Phase 1/2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Immunogenicity, and Viral Shedding of MEDI-559, a Live Attenuated Intranasal Vaccine Against Respiratory Syncytial Virus in Healthy 1 to <24 Month-Old Children

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Biological: MEDI-559
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female whose age on the day of randomization falls within one of the two age cohorts: Cohort 1: 5 to <24 months (reached their 5th month birthday but not yet reached their 2nd year birthday); Cohort 2: 1 to < 3 months (>28 days of age and not yet reached their 3rd month birthday) Cohort 1 only: Subject is seronegative to RSV at screening Subject was the product of normal full term pregnancy (defined as 36-42 weeks gestation) Subject is in general good health Written informed consent and HIPAA authorization (if applicable) obtained from the subject's legal representative Subject's legal representative is willing and able to bring the subject to the study site for evaluation of respiratory illness in accordance with the protocol Exclusion Criteria: Any fever (≥ 100.4°F [≥ 38.0°C]), regardless of route within 7 days prior to randomization Acute illness (defined as the presence of moderate or severe signs and symptoms) at the time of randomization Moderate or severe nasal congestion that in the investigator's opinion could prevent intranasal delivery of vaccine Cohort 1 only: weight ≤ 5th percentile for age on the day of randomization Cohort 2 only: history of low birth weight (ie, <2500 grams at birth) or weight ≤ 5th percentile for age on the day of randomization Living in the same home or enrolled in the same classroom at day care with infants <6 months of age within 28 days after each dose (only one child per household may be enrolled into the study) Contact with pregnant caregiver within 28 days after each dose Living in a household with someone who is immunocompromised within 28 days after each dose; the subject should also avoid close contact with immunocompromised individuals for at least 28 days after each study vaccine dosing Living in a household with someone who works in the healthcare field and who has direct patient care responsibilities within 28 days after each dose Living in a household with someone who is a day care provider or preschool teacher for children <6 months of age within 28 days after each dose

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 23 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 MEDI-559<br>MEDI-559 | Biological: MEDI-559<br>* Cohort 1 (5 to <24 months): N=80 MEDI-559 at 10^5 FFU at 0, 2, and 4 months; frozen preparation filled into 0.5 ml luer slip-tip syringes. Each 0.2 ml dose contains 10^5 FFU MEDI-559 in a sucrose phosphate glutamate buffer.<br>|
| Placebo Comparator: Cohort 1 Placebo<br>Placebo | Other: Placebo<br>* Cohort 1 (5 to < 24 months); N = 80 placebo at 0, 2, and 4 months; frozen preparation filled into 0.5 ml luer slip-tip syringes. Each 0.2 ml dose contains sucrose phosphate buffer.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of solicited symptoms after Dose 1 | Solicited symptoms are predefined symptoms or events to be specifically inquired about and assessed daily during the 28-day period after vaccine administration. The solicited symptoms for this study include: fever >100.4°F (>38.0 °C) regardless of route, runny/stuffy nose, cough, drowsiness, loss of appetite/decreased urine output, irritability/Fussiness, oropharyngeal irritation (laryngitis), epistaxis | Through Day 28 after each dose | 
| Incidence of solicited symptoms after Dose 2 | Solicited symptoms are predefined symptoms or events to be specifically inquired about and assessed daily during the 28-day period after vaccine administration. The solicited symptoms for this study include: fever >100.4°F (>38.0 °C) regardless of route, runny/stuffy nose, cough, drowsiness, loss of appetite/decreased urine output, irritability/Fussiness, oropharyngeal irritation (laryngitis), epistaxis | Through Day 28 after each dose | 
| Incidence of solicited symptoms after Dose 3 | Solicited symptoms are predefined symptoms or events to be specifically inquired about and assessed daily during the 28-day period after vaccine administration. The solicited symptoms for this study include: fever >100.4°F (>38.0 °C) regardless of route, runny/stuffy nose, cough, drowsiness, loss of appetite/decreased urine output, irritability/Fussiness, oropharyngeal irritation (laryngitis), epistaxis | Through Day 28 after each dose | 
| Incidence of adverse events (AEs) after Dose 1 | As defined by the ICH Guideline for Good Clinical Practice, an AE is: Any untoward medical occurrence in a participant or clinical investigations subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event (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. | Through Day 28 after each dose | 
| Incidence of AEs after Dose 2 | As defined by the ICH Guideline for Good Clinical Practice, an AE is: Any untoward medical occurrence in a participant or clinical investigations subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event (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. | Through Day 28 after each dose | 
| Incidence of AEs after Dose 3 | As defined by the ICH Guideline for Good Clinical Practice, an AE is: Any untoward medical occurrence in a participant or clinical investigations subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event (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. | Through Day 28 after each dose | 
| Incidence of medically-attended lower respiratory illnesses (MA-LRIs) after Dose 1 | An MA-LRI is defined as a health care provider confirmed diagnosis of any one or more of the following events: wheezing, pneumonia, croup (laryngotracheobronchitis), rhonchi (not cleared with cough or suctioning), rales (not cleared with cough or suctioning), bronchitis, bronchiolitis, apnea | Through Day 28 after each dose | 
| Incidence of MA-LRIs after Dose 2 | An MA-LRI is defined as a health care provider confirmed diagnosis of any one or more of the following events: wheezing, pneumonia, croup (laryngotracheobronchitis), rhonchi (not cleared with cough or suctioning), rales (not cleared with cough or suctioning), bronchitis, bronchiolitis, apnea | Through Day 28 after each dose | 
| Incidence of MA-LRIs after Dose 3 | An MA-LRI is defined as a health care provider confirmed diagnosis of any one or more of the following events: wheezing, pneumonia, croup (laryngotracheobronchitis), rhonchi (not cleared with cough or suctioning), rales (not cleared with cough or suctioning), bronchitis, bronchiolitis, apnea | Through Day 28 after each dose | 
| Incidence of SAEs | An SAE is any adverse event 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 subject); an important medical event that may not result in death, threaten life or require hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, it may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above. | Administration of Dose 1 (Day 0) through Day 28 post final dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of MEDI-559 shedding | Number (%) of subjects who shed vaccine-type virus | Day 7-10 after Dose 1, 2, and 3 | 
| Incidence of MEDI-559 shedding | Number (%) of subjects who shed vaccine-type virus | Day 12-18 after Dose 1, 2, and 3 | 
| Incidence of MEDI-559 shedding | Number (%) of subjects who shed vaccine-type virus | Day 28-34 post Dose 1, 2, and 3 | 
| Post-vaccination seroresponse against RSV | Seroresponse is defined as a ≥ 4-fold rise from baseline as measured by microneutralization assay | Day 28 post final dose | 
| Phenotypic stability of recovered vaccine-type virus | Number (%) of nasal wash samples containing vaccine-type virus that is found to be phenotypically stable | Day 7-10 post any dose | 
| Phenotypic stability of recovered vaccine-type virus | Number (%) of nasal wash samples containing vaccine-type virus that is found to be phenotypically stable | Day 12-18 post any dose | 
| Phenotypic stability of recovered vaccine-type virus | Number (%) of nasal wash samples containing vaccine-type virus that is found to be phenotypically stable | Day 28-34 post any dose | 
| Genotypic stability of recovered vaccine-type virus | Number (%) of nasal wash samples containing vaccine-type virus that is found to be genotypically stable | Day 7-10 post any dose | 
| Genotypic stability of recovered vaccine-type virus | Number (%) of nasal wash samples containing vaccine-type virus that is found to be genotypically stable | Day 12-18 post any dose | 
| Genotypic stability of recovered vaccine-type virus | Number (%) of nasal wash samples containing vaccine-type virus that is found to be genotypically stable | Day 28-34 post any dose | 
| Incidence of MA-LRIs | Number (%) of subjects with MA-LRIs occurring from Study Day 0 through the end of study | Study Day 0 through 365 days post randomization | 
| Incidence of SAEs | Number (%) of subjects with SAEs occurring from Study Day 0 through 365 days post randomization | Study Day 0 post Dose 1 through 365 days post randomization | 
| Incidence of significant new medical conditions (SNMCs) | Number (%) of subjects with SNMCs from administration of Dose 1 through 365 days post randomization | Study Day 0 post Dose 1 through 365 days post randomization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MEDI-559, Respiratory Syncytial Virus, RSV, Pediatric, Vaccine, respiratory syncytial virus, RSV, pediatric, vaccine