A PHASE 2B PLACEBO-CONTROLLED, RANDOMIZED STUDY OF A RESPIRATORY SYNCYTIAL VIRUS (RSV) VACCINE IN PREGNANT WOMEN

Study Overview
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Brief Summary
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This Phase 2b study will evaluate the safety, tolerability, and immunogenicity of an RSV vaccine in pregnant participants who receive either one of 2 dose levels of the vaccine, formulated with or without aluminum hydroxide, or placebo, and investigate safety and characteristics of antibodies in their infants.

Detailed Description
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This Phase 2b, multicenter, randomized, placebo-controlled study will evaluate the safety, tolerability, and immunogenicity of a respiratory syncytial virus stabilized prefusion F subunit vaccine (RSV vaccine) in pregnant participants who receive either one of 2 dose levels of the vaccine, formulated with or without aluminum hydroxide, or placebo, as well as assess safety and characteristics of transplacentally transferred antibodies in their infants.

Official Title
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A PHASE 2B, RANDOMIZED, PLACEBO-CONTROLLED, OBSERVER-BLINDED TRIAL TO EVALUATE THE SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF A RESPIRATORY SYNCYTIAL VIRUS (RSV) VACCINE IN PREGNANT WOMEN 18 THROUGH 49 YEARS OF AGE AND THEIR INFANTS

Conditions
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Respiratory Tract Infection

Intervention / Treatment
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* Biological: RSV vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - Maternal participants: Healthy women 18 to 49 years of age between 24 and 36 weeks of gestation on the day of planned vaccination, with an uncomplicated pregnancy, who are at no known increased risk for complications, and whose fetus has no significant abnormalities observed on ultrasound. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Receiving prenatal standard of care. Had an ultrasound performed at >=18 weeks of pregnancy. Had a negative urinalysis for protein and glucose at the screening visit. Trace protein in the urine is acceptable if the blood pressure is also normal. Determined by medical history, physical examination, screening laboratory assessment, and clinical judgment to be appropriate for inclusion in the study. Documented negative human immunodeficiency virus antibody, hepatitis B virus surface antigen, hepatitis C virus antibody, and syphilis tests at the screening visit. Body mass index of </=40 kg/m2 at the time of the screening visit. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent document and in this protocol. Expected to be available for the duration of the study and willing to give informed consent for her infant to participate in the study. Inclusion Criteria - Infant Participants: Evidence of a signed and dated ICD signed by the parent(s). Parent(s) willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Exclusion Criteria - Maternal Participants: Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction to any component of the investigational product or any related vaccine. History of latex allergy. History of any severe allergic reaction. Participants with known or suspected immunodeficiency. Current pregnancy resulting from in vitro fertilization or other assisted reproductive technology. A prior history of or known current pregnancy complications or abnormalities that will increase the risk associated with the participant's participation in and completion of the study. Major illness of the mother or conditions of the fetus that, in the investigator's judgment, will substantially increase the risk associated with the participant's participation in, and completion of, the study or could preclude the evaluation of the participant's response. Participant with a history of autoimmune disease or an active autoimmune disease requiring therapeutic intervention including but not limited to systemic or cutaneous lupus erythematosus, autoimmune arthritis/rheumatoid arthritis, Guillain-Barré syndrome, multiple sclerosis, Sjögren's syndrome, idiopathic thrombocytopenia purpura, glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis), psoriasis, and insulin-dependent diabetes mellitus (type 1). Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. Participation in other studies involving investigational drug(s) within 28 days prior to study entry and/or during study participation. Participants who receive treatment with immunosuppressive therapy including cytotoxic agents or systemic corticosteroids (such as for cancer or an autoimmune disease), or planned receipt of such treatment or agents during study participation. If systemic corticosteroids have been administered short term (<14 days) for treatment of an acute illness, participants should not be enrolled into the study until corticosteroid therapy has been discontinued for at least 30 days before investigational product administration. Inhaled/nebulized, intra articular, intrabursal, or topical (skin or eyes) corticosteroids are permitted. Current alcohol abuse or illicit drug use. Receipt of blood or plasma products or immunoglobulin, from 60 days before investigational product administration, or planned receipt through delivery, with 1 exception, Rho(D) immune globulin (eg, RhoGAM), which can be given at any time. Previous vaccination with any licensed or investigational RSV vaccine or planned receipt during study participation. Laboratory test results at the screening visit outside the normal reference value for pregnant women according to their trimester in pregnancy. Participants who are breastfeeding at the time of the screening visit. Exclusion Criteria - Infant Participants: • Infant who is a direct descendant (eg, child or grandchild) of the study personnel.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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 |
| --- | --- |
| Experimental: RSV dose with aluminum hydroxide<br>RSV vaccine with aluminum hydroxide | Biological: RSV vaccine<br>* RSV vaccine<br>|
| Experimental: RSV dose without aluminum hydroxide<br>RSV vaccine without aluminum hydroxide | Biological: RSV vaccine<br>* RSV vaccine<br>|
| Experimental: Higher RSV dose with aluminum hydroxide<br>Higher dose level RSV vaccine with aluminum hydroxide | Biological: RSV vaccine<br>* RSV vaccine<br>|
| Experimental: Higher RSV dose without aluminum hydroxide<br>Higher dose level RSV vaccine without aluminum hydroxide | Biological: RSV vaccine<br>* RSV vaccine<br>|
| Placebo Comparator: Placebo dose<br>Normal saline solution for injection (0.9% sodium chloride injection) | Biological: Placebo<br>* Normal saline solution for injection (0.9% sodium chloride injection)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Maternal Participants With Prespecified Local Reactions by Maximum Severity Within 7 Days After Vaccination | Local reactions included pain at injection site, redness and swelling and were recorded by participants in an electronic diary (e-diary). Redness and swelling were measured and recorded in measuring device units. 1 measuring device unit =0.5 centimeter (cm) and graded as mild: greater than (>) 2.0 to 5.0 cm, moderate: >5.0 to 10.0 cm and severe: >10.0 cm. Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfered with daily activity and severe: prevented daily activity. The maximum severity was defined as highest grading of each local reaction within 7 days of vaccination. | Within 7 days after vaccination | 
| Percentage of Maternal Participants With Prespecified Systemic Events by Maximum Severity Within 7 Days After Vaccination | Systemic events included fever, fatigue, headache, nausea, muscle pain, joint pain, vomiting, diarrhea and were recorded by participants in an e-diary. Fever was categorized as: grade 1: mild (>=38.0 to 38.4 degrees [deg] Celsius [C]), grade 2: moderate (>38.4 to 38.9 deg C), grade 3: severe (>38.9 to 40.0 deg C) and grade 4 (>40.0 deg C). Fatigue, headache, nausea, muscle pain and joint pain were graded as mild: did not interfere with activity, moderate: some interference with activity and severe: prevented daily routine activity. Vomiting was graded as mild: 1 to 2 times in 24 hours(h), moderate: >2 times in 24h and severe: required intravenous hydration. Diarrhea was graded as mild: 2 to 3 loose stools in 24h, moderate: 4 to 5 loose stools in 24h and severe: 6 or more loose stools in 24h. The maximum severity was defined as highest grading of each systemic event within 7 days of vaccination. | Within 7 days after vaccination | 
| Percentage of Maternal Participants With Adverse Events (AEs) Within 1 Month After Vaccination | An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. AEs included both serious and non-serious adverse events. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect. | Within 1 month after vaccination | 
| Percentage of Maternal Participants With Serious Adverse Events (SAEs), Medically Attended Adverse Events (MAEs) and Obstetric Complications | MAE was defined as a non-serious AE that results in an evaluation at a medical facility. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect. Obstetric complications were determined as per the study clinician's judgement. | From day of vaccination (Day 1) up to 12 months post-delivery | 
| Percentage of Infant Participants With Specific Birth Complications | Specific birth complications included clavicle fracture, torticollis, cephalhematoma, premature baby, acute respiratory failure, meconium aspiration syndrome, neonatal pneumothorax, neonatal respiratory depression, neonatal respiratory distress, neonatal respiratory distress syndrome, neonatal respiratory failure, pneumothorax, respiratory distress, transient tachypnea of the newborn and subgaleal hemorrhage. Percentage of participants with any specific birth complications were reported in this outcome measure. | At birth | 
| Percentage of Infant Participants With Any AE Within 1 Month of Age | An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. AEs included both serious and non-serious adverse events. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect. | Within 1 month after birth | 
| Percentage of Infant Participants With MAEs and SAEs Within 12 Months of Age | MAE was defined as a non-serious AE that results in an evaluation at a medical facility. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect. | Within 12 months after birth | 
| Percentage of Infant Participants With AEs of Special Interest of at Least Moderate Severity Within 12 Months of Age: Congenital Anomalies and Developmental Delay | AEs of special interest for infant participants included congenital anomalies and developmental delays. Congenital anomalies were defined as structural or functional anomalies that occurred during intrauterine life and could be identified prenatally, at birth or later in life. Severity was assessed based on the study investigator's judgement and graded as grade 1= mild (does not interfere with participant's usual function); grade 2= moderate (interferes to some extent with participant's usual function); grade 3= severe (interferes significantly with participant's usual function) and grade 4= life-threatening (life-threatening consequences; urgent intervention indicated). Percentage of infant participants with AEs of special interest of at least moderate severity were presented. | Within 12 months after birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titer (GMT) of Respiratory Syncytial Virus Subgroup A (RSV A) and Subgroup B (RSV B) Neutralizing Antibodies in Maternal Participants | GMT of the 50% RSV A and RSV B neutralizing antibody were calculated by exponentiating the mean logarithm of the titers and the corresponding 95% confidence interval (CI) was based on the Student t distribution. Geometric mean ratios (GMRs) of the RSV vaccine group to the placebo group for the RSV A and RSV B neutralizing antibody titers at each time point was calculated and reported in statistical analysis. | Before vaccination, 2 weeks and 1 month after vaccination and at delivery | 
| Geometric Mean Fold Rise (GMFR) for Respiratory Syncytial Virus Subgroup A (RSV A) and Subgroup B (RSV B) Neutralizing Antibody Titers in Maternal Participants | GMFRs for RSV A and RSV B neutralizing antibody titers from before vaccination to each available time point after vaccination were calculated by exponentiating the mean logarithm of the fold rises. Corresponding 95% CI was based on the Student t distribution. Data for this outcome measure was planned to be analyzed for maternal participants only. | 2 weeks and 1 month after vaccination, at delivery | 
| Geometric Mean Titer (GMT) of Respiratory Syncytial Virus Subgroup A (RSV A) and Subgroup B (RSV B) Neutralizing Antibodies in Infant Participants | GMT of the 50% RSV A and RSV B neutralizing antibody were calculated by exponentiating the mean logarithm of the titers and the corresponding 95% CI was based on the Student t distribution. GMRs of the RSV vaccine group to the placebo group for the RSV A and RSV B neutralizing antibody titers at each time point was calculated and reported in statistical analysis. | At birth and at 1, 2, 4, 6 months after birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Respiratory tract infection, Respiratory Syncytial Virus, RSV, Vaccine