Clinical trial NCT02624947: A Study to Determine the Safety and Efficacy of the RSV F Vaccine to Protect Infants Via Maternal Immunization
Official title: A Phase 3, Randomized, Observer-Blind, Placebo-Controlled, Group-Sequential Study to Determine the Immunogenicity and Safety of a Respiratory Syncytial Virus (RSV) F Nanoparticle Vaccine With Aluminum in Healthy Third-trimester Pregnant Women; and Safety and Efficacy of Maternally Transferred Antibodies in Preventing RSV Disease in Their Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Respiratory Syncytial Virus Infections
Keywords: RSV
Lead sponsor: Novavax
Sponsor class: INDUSTRY
Collaborators: name: Bill and Melinda Gates Foundation
First posted: 2015-12-09
Enrollment: 4636
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine the efficacy of maternal immunization during the third trimester of pregnancy with the RSV F vaccine against medically-significant RSV lower respiratory tract infection (LRTI), as defined by hypoxemia or tachypnea at rest, through the first 90, 120, 150, and 180 days of life in infants.

Detailed description: This is a randomized, observer-blind, placebo-controlled trial enrolling third-trimester pregnant women in the Northern and Southern hemispheres, for up to four consecutive RSV seasons in each hemisphere. The trial could enroll up to 8618 third-trimester pregnant subjects, of which 4,636 were actually enrolled. Women in the third trimester of a singleton uncomplicated low-risk pregnancy and 18 to 40 years of age (inclusive) were enrolled and randomized in a 1:1 ratio into one of two treatment groups, active or placebo, over approximately three months prior to peak RSV season in their locale. After the first global season of enrollment, the randomization scheme was changed to a 2:1 (active/placebo) ratio to enable a more efficient accrual of the safety database.

All maternal subjects were to receive a single intramuscular (IM) injection on Day 0 with the assigned test article, the RSV F vaccine, or placebo. Study participation for maternal subjects spanned approximately nine (9) months from the first dose, ending six (6) months post-delivery. Study follow-up for live-born infant subjects spanned approximately one (1) year post-delivery.

Eligibility criteria: Inclusion Criteria:

1. ≥18 and ≤40 years-of-age
2. Singleton pregnancy of 28 to 36 0/7 weeks gestation on the day of planned vaccination

   * Documentation of gestational age will be based on one of the following composite criteria. (Note: The Investigator was to use the earliest ultrasound data available to establish the study-specific gestational age dating):

     1. Gestational Age Dating Based on First Trimester Data (data obtained ≤13 6/7 weeks): The date of the first day of the reported last menstrual period (LMP) may be used to establish the gestational age if corroborated by a first trimester ultrasound. If the gestational age estimation derived using the LMP and the first trimester ultrasound are discrepant \>7 days, the ultrasound will be used to establish gestational age. If LMP is uncertain or unknown, the ultrasound-established gestational age estimation will be used to establish the gestational age of the pregnancy.
     2. Gestational Age Dating Based on Early Second Trimester Data (data obtained 14 0/7 to 21 6/7 weeks): The day of the first reported LMP may be used to establish the gestational age if corroborated by an early second trimester ultrasound (that estimates the gestational age between 14 0/7 and 21 6/7 weeks). If the gestational age estimation derived using the LMP and the early second trimester ultrasound are discrepant \>10 days, the ultrasound will be used to establish the gestational age. If LMP is uncertain or unknown, the ultrasound-established gestational age estimation will be used to establish the gestational age of the pregnancy.
     3. Gestation Age Dating Based on Later Second Trimester Data (data obtained 22 0/7 and 27 6/7 weeks by LMP): The date of the first day of the reported LMP may be used to establish the gestation age if corroborated by a later second trimester ultrasound (that estimates the gestational age between 22 0/7 and 27 6/7 weeks). If the gestational age estimation derived using the LMP and the later second trimester ultrasound are discrepant \>14 days, the ultrasound will be used to establish the gestational age. If LMP is uncertain or unknown, the ultrasound-established gestational age estimation will be used to establish the gestational age of the pregnancy.
     4. Gestational Age Dating When the LMP is Uncertain or Unknown AND No Prior First or Second Trimester Ultrasound Has Been Performed: An ultrasound performed at screening within the second trimester (≤27 6/7 weeks) will be used to establish the gestational age of the pregnancy.
3. Documentation of a second or third (between 18 0/7 weeks and prior to randomization) trimester ultrasound with no major fetal anomalies identified.
4. Good general maternal health as demonstrated by:

   * Medical history (including history of adverse reactions to prior vaccines and allergies).
   * Physical examination including at least vital signs (blood pressure, pulse, respirations, and oral temperature); weight; height; examination of the HEENT, cardiovascular, pulmonary, gastrointestinal (abdominal), musculoskeletal, lymphatic, and dermatologic organ systems; and documentation of fetal heart tones. Note that abnormal vital signs may be repeated at the investigator's discretion since these measures may be labile. Vital signs should be assessed in the context of normal values for the third trimester of pregnancy (see the Study Operations Manual).
   * Clinical laboratory parameters that include:

     * For the first year of study conduct in any country, normal/clinically insignificant blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase (ALP), hemoglobin, white blood count, and platelet count. Note that normal ranges for clinical laboratory parameters will be based on reference ranges appropriate for the subject population under study (i.e., third trimester of pregnancy) and as defined in the toxicity grading scale (TGS) (see the Study Operations Manual).
     * For all subjects, serologic exclusion of infection with hepatitis B (HBV) and C (HCV) viruses, syphilis, and HIV as documented by testing (performed at the central or local laboratory) at screening or by medical records during the current pregnancy.
5. Able to understand, and both willing and physically able to comply with study procedures. This includes anticipation of reasonable geographic proximity to the study clinic and adequate transportation to comply with scheduled and unscheduled study follow-up visits.
6. Able and willing to provide written informed consent for themselves and infant.

Exclusion Criteria:

1. Symptomatic cardiac or pulmonary disease requiring chronic drug therapy, including hypertension and asthma. Asthma will be exclusionary if the subject is receiving chronic systemic glucocorticoids at any dose or inhaled glucocorticoids at any dose \>500µg per day of beclomethasone or fluticasone, or \>800μg per day of budesonide.
2. Pregnancy complications (in the current pregnancy) such as preterm labor, hypertension (blood pressure \[BP\] \>140/90 in the presence of proteinuria or BP \>150/100 with or without proteinuria) or currently on an antihypertensive therapy or pre-eclampsia; or evidence of intrauterine growth restriction.
3. Grade 2 or higher clinical laboratory or vital sign abnormality. Exclusion of subjects with grade 1 abnormalities will be based on the subject's prior medical history and the investigator's clinical judgment that the abnormality is indicative of a meaningful physiologic event.
4. Receipt of any licensed vaccine (e.g., Tdap, inactivated influenza vaccine) within 14 days of study vaccination.
5. Received any RSV vaccine at any time.
6. Body mass index (BMI) of ≥40, at the time of the screening visit.
7. Hemoglobinopathy (even if asymptomatic) or blood dyscrasias.
8. Hepatic or renal dysfunction.
9. Established diagnosis of seizure disorder, regardless of therapy.
10. Known, active auto-immune disease or immunodeficiency syndrome.
11. Endocrine disorders, including (but not limited to) untreated hyperthyroidism, untreated hypothyroidism (unless due to auto-immune disease), and glucose intolerance (e.g., diabetes mellitus type 1 or 2) antedating pregnancy, or occurring during pregnancy and requiring interventions other than diet for control.
12. History of major gynecologic or major abdominal surgery, including bariatric surgery (previous Caesarean section is not an exclusion).
13. Known HIV, syphilis, HBV, or HCV infection, as assessed by serologic tests conducted during the current pregnancy or as a procedure during the screening period of the study.
14. Primary genital Herpes simplex virus (HSV) infection during the current pregnancy.
15. Current alcohol or drug abuse based on the Investigator's knowledge of present or recent (within the last 2 years) use/abuse of alcohol or illegal or non-prescription drugs.
16. Documentation that the current pregnancy results from in vitro fertilization (IVF).
17. Documentation that the current pregnancy results from rape or incest.
18. Documentation that the infant will be a ward of the state or be released for adoption.
19. History/presence of deep venous thrombosis or thromboembolism, or the use of anticoagulants during pregnancy (the use of low-dose aspirin as prophylaxis \[e.g., for the prevention of morbidity and mortality from preeclampsia\] is acceptable is dosages consistent with local standards of care).
20. Red blood cell allo-immunization.
21. Prior stillbirth or neonatal death, or multiple (≥3) spontaneous abortions.
22. Prior preterm delivery ≤34 weeks gestation or having ongoing intervention (medical/surgical) in current pregnancy to prevent preterm birth.
23. Greater than five (5) prior deliveries.
24. Previous infant with a known genetic disorder or major congenital anomaly.
25. Receipt of investigational drugs or immune globulins (with the exception of prophylactic anti-Rho D immune globulin) within six (6) months prior to the administration of the study vaccine.
26. Chronic administration (defined as more than 14 continuous days) of immunosuppressants or other immune-modifying drugs within 6 months prior to the administration of the study vaccine. An immunosuppressant dose of glucocorticoid will be defined as a systemic dose ≥10mg of prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids will be permitted except for the limit established in exclusion criterion #1.
27. Neuro-psychiatric illness deemed likely to interfere with protocol compliance, safety reporting, or receipt of pre-natal care; or requiring treatment with psychotropic drugs (excluding treatment for depression and anxiety).
28. Any other physical, psychiatric or social condition which may, in the investigator's opinion, increase the risks of study participation to the maternal subject or the fetus/infant; or may lead to the collection of incomplete or inaccurate safety data.
29. Acute disease within 72 hours of the day of the planned vaccination (defined as the presence of a moderate or severe illness with or without fever, or an oral temperature \>38.0°C).
30. History of a serious adverse reactions (e.g., anaphylaxis) to any prior vaccine.

Primary outcomes:
measure: Infants: Percentages of Participants With Medically Significant RSV LRTI With Either Hypoxemia (SpO2 <95% at Sea Level or <92% at Altitudes >1800 Meters) or Tachypnea
timeFrame: Delivery to 180 days after delivery
Secondary outcomes:
measure: Infants: Number of Participants With RSV LRTI With Severe Hypoxemia (Sp02 <92% at Sea Level or <87% at Altitudes >1800 Meters) or Documented Use of Oxygen by High Flow Nasal Cannula or Other Advanced Respiratory Support Through 90 Days of Life
timeFrame: Delivery to 180 days after delivery
measure: Infants: Percentages of Participants With RSV LRTI With Hospitalization From Delivery
timeFrame: Delivery to 180 days after delivery
measure: Infant: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Neonatal Period and Through the First Year of Life
timeFrame: Delivery to 364 days after delivery
measure: Infants: Number of Participants With Potential Developmental Delay
timeFrame: Day 180 after delivery
measure: Maternal: Number of Participants With Solicited Injection Site and Systemic Reactogenicity
timeFrame: Day 0 to Day 7
measure: Maternal: Number of Participants With Unsolicited Adverse Events, Medically-attended Adverse Events (MAEs), Significant New Medical Conditions (SNMCs) and Serious Adverse Events (SAEs)
timeFrame: Delivery to 180 days after delivery
measure: Maternal: Number of Participants With Caesarean, Vaginal, or Instrument Assisted Vaginal Modes of Delivery
timeFrame: Delivery
measure: Maternal: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMFR
timeFrame: Day 14 to Delivery
measure: Maternal: Percentage of Participants With a Seroresponse to RSV F Vaccine and Placebo
timeFrame: Day 14 to Delivery
measure: Maternal: Percentage of Participants Who Seroconverted (2 Fold Increase) as Determined by Immunogenicity of RSV F Vaccine and Placebo
timeFrame: Day 14 to Delivery
measure: Maternal: Percentage of Participants Who Seroconverted (4 Fold Increase) as Determined by Immunogenicity of RSV F Vaccine and Placebo
timeFrame: Day 14 to Delivery
measure: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMT
timeFrame: Delivery to Day 180
measure: Infants: Percentage of Participants With a Seroresponse to RSV F Vaccine and Placebo
timeFrame: Delivery to Day 180
measure: Infant: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMR
timeFrame: Day 14 to Day 180
measure: Infants: Mean Length of Participants at Birth
timeFrame: At Delivery
measure: Infants: Mean Weight of Participants at Birth
timeFrame: At Delivery
measure: Infants: Mean Frontal-occipital Head Circumference of Participants at Birth
timeFrame: At Delivery
measure: Infants: Mean APGAR (Appearance, Pulse, Grimace, Activity, Respiration) Score of Participants at Birth
timeFrame: At Delivery
measure: Maternal: Number of Participants With Post-immunization Onset of Specific Complications of Third-trimester Pregnancy and Delivery
timeFrame: Day 0 to Delivery
measure: Infants: Number of Participants With Developmental Delay
timeFrame: Day 364 after delivery
measure: Maternal: Immunogenicity of Anti-RSV F IgG and Placebo Expressed as GMEU (Geometric Mean ELISA Units/mL)
timeFrame: Pre-dose to Delivery +180 days
measure: Maternal: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMC (Geometric Mean Concentration)
timeFrame: Pre-dose to Delivery +180 days
measure: Maternal: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMT (Geometric Mean Titers)
timeFrame: Pre-dose to Delivery +180 days
measure: Maternal: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMTs
timeFrame: Pre-dose to Delivery +180 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Research Site US115
state: Alabama
city: Cullman
country: United States
facility: Research Site US035
state: Alabama
city: Fort Defiance
country: United States
facility: Research Site US130
state: Arizona
city: Phoenix
country: United States
facility: Research Site US123
state: Arizona
city: Tucson
country: United States
facility: Research Site US103
state: Arizona
city: Whiteriver
country: United States
facility: Research Site US129
state: Arizona
city: Colton
country: United States
facility: Research Site US092
state: California
city: Huntington Park
country: United States
facility: Research Site US114
state: California
city: Los Angeles
country: United States
facility: Research Site US127
state: California
city: Madera
country: United States
facility: Research Site US091
state: California
city: Riverside
country: United States
facility: Research Site US093
state: California
city: Aurora
country: United States
facility: Research Site US134
state: Colorado
city: Denver
country: United States
facility: Research Site US036
state: Colorado
city: Washington
country: United States
facility: Research Site US040
state: District of Columbia
city: Blackfoot
country: United States
facility: Research Site US037
state: Idaho
city: Idaho Falls
country: United States
facility: Research Site US119
state: Idaho
city: Nampa
country: United States
facility: Research Site US032
state: Idaho
city: Chicago
country: United States
facility: Research Site US095
state: Illinois
city: West Des Moines
country: United States
facility: Research Site US090
state: Iowa
city: Augusta
country: United States
facility: Research Site US038
state: Kansas
city: Hutchinson
country: United States
facility: Research Site US031
state: Kansas
city: Louisville
country: United States
facility: Research Site US096
state: Kentucky
city: Alexandria
country: United States
facility: Research Site US126
state: Louisiana
city: Metairie
country: United States
facility: Research Site US039
state: Louisiana
city: Detroit
country: United States
facility: Research Site US101
state: Michigan
city: Biloxi
country: United States
facility: Research Site US098
state: Mississippi
city: Lincoln
country: United States
facility: Research Site US102
state: Nebraska
city: Norfolk
country: United States
facility: Research Site US025
state: Nebraska
city: Neptune
country: United States
facility: Research Site US088
state: New Jersey
city: Gallup
country: United States
facility: Research Site US131
state: New Mexico
city: Johnson City
country: United States
facility: Research Site US087
state: New York
city: Syracuse
country: United States
facility: Research Site US086
state: New York
city: Durham
country: United States
facility: Research Site US020
state: North Carolina
city: Fort Bragg
country: United States
facility: Research Site US097
state: North Carolina
city: Englewood
country: United States
facility: Research Site US089
state: Ohio
city: Pittsburgh
country: United States
facility: Research Site US021
state: Pennsylvania
city: Beaumont
country: United States
facility: Research Site US116
state: Texas
city: Fort Worth
country: United States
facility: Research Site US083
state: Texas
city: Galveston
country: United States
facility: Research Site US043
state: Texas
city: Houston
country: United States
facility: Research Site US019
state: Texas
city: Houston
country: United States
facility: Research Site US128
state: Texas
city: Lampasas
country: United States
facility: Research Site US125
state: Texas
city: Longview
country: United States
facility: Research Site US094
state: Texas
city: San Antonio
country: United States
facility: Research Site US042
state: Texas
city: Salt Lake City
country: United States
facility: Research Site US121
state: Utah
city: Salt Lake City
country: United States
facility: Research Site US008
state: Utah
city: Salt Lake City
country: United States
facility: Research Site US099
state: Utah
city: Richmond
country: United States
facility: Research Site US100
state: Virginia
city: Seattle
country: United States
facility: Research Site US041
state: Washington
city: Buenos Aires
country: Argentina
facility: Research Site AR002
city: Cordoba
country: Argentina
facility: Research Site AR006
city: Mendoza
country: Argentina
facility: Research Site AR011
city: Salta
country: Argentina
facility: Research Site AR008
city: Tucuman
country: Argentina
facility: Research Site AR003
city: Brisbane
country: Australia
facility: Research Site AU010
state: Queensland
city: Adelaide
country: Australia
facility: Research Site AU007
state: South Australia
city: Clayton
country: Australia
facility: Research Site AU011
state: Victoria
city: Melbourne
country: Australia
facility: Research Site AU008
state: Victoria
city: Perth
country: Australia
facility: Research Site AU009
state: Western Australia
city: Sylhet
country: Bangladesh
facility: Research Site BD001
state: Sylhet Division
city: Santiago
country: Chile
facility: Research Site CL001
state: Region Metropolitana (RM)
city: Concepcion
country: Chile
facility: Research Site CL003
state: VIII Region
city: Osorno
country: Chile
facility: Research Site CL002
state: X Region
city: Monterrey
country: Mexico
facility: Research Site MX001
state: Nuevo Leon
city: Grafton
country: New Zealand
facility: Research Site NZ003
state: Auckland
city: Papatoetoe
country: New Zealand
facility: Research Site NZ001
state: Aukland
city: Christchurch
country: New Zealand
facility: Research Site NZ002
city: Wellington
country: New Zealand
facility: Research Site NZ004
city: Alabang
country: Philippines
facility: Research Site PH001
state: Manila
city: Muntinlupa
country: Philippines
facility: Research Site PH002
state: Metro Manila
city: Parow
country: South Africa
facility: Research Site ZA004
state: Cape Town
city: Hillbrow
country: South Africa
facility: Research Site ZA003
state: Johannesburg
city: Thabazimbi
country: South Africa
facility: Research Site ZA007
state: Limpopo Providence
city: Bellville
country: South Africa
facility: Research Site ZA010
state: Western Cape
city: Paarl
country: South Africa
facility: Research Site ZA009
state: Western Cape
city: Worcester
country: South Africa
facility: Research Site ZA011
state: Western Cape
city: Benoni
country: South Africa
facility: Research Site ZA006
city: Bloemfontein
country: South Africa
facility: Research Site ZA008
city: Soshanguve
country: South Africa
facility: Research Site ZA002
city: Soweto
country: South Africa
facility: Research Site ZA001
city: Barcelona
country: Spain
facility: Research Site ES002
city: Madrid
country: Spain
facility: Research Site ES003
city: Santiago de Compostela
country: Spain
facility: Research Site ES004
city: Sevilla
country: Spain
facility: Research Site ES001
city: Bristol
country: United Kingdom
facility: Research Site UK004
city: London
country: United Kingdom
facility: Research Site UK001
city: Oxford
country: United Kingdom
facility: Research Site UK002
city: Southampton
country: United Kingdom
facility: Research Site UK003
Study officials:
affiliation: Novavax Inc
name: Clinical Development
role: STUDY_DIRECTOR
References:
citation: Madhi SA, Polack FP, Piedra PA, Munoz FM, Trenholme AA, Simoes EAF, Swamy GK, Agrawal S, Ahmed K, August A, Baqui AH, Calvert A, Chen J, Cho I, Cotton MF, Cutland CL, Englund JA, Fix A, Gonik B, Hammitt L, Heath PT, de Jesus JN, Jones CE, Khalil A, Kimberlin DW, Libster R, Llapur CJ, Lucero M, Perez Marc G, Marshall HS, Masenya MS, Martinon-Torres F, Meece JK, Nolan TM, Osman A, Perrett KP, Plested JS, Richmond PC, Snape MD, Shakib JH, Shinde V, Stoney T, Thomas DN, Tita AT, Varner MW, Vatish M, Vrbicky K, Wen J, Zaman K, Zar HJ, Glenn GM, Fries LF; Prepare Study Group. Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants. N Engl J Med. 2020 Jul 30;383(5):426-439. doi: 10.1056/NEJMoa1908380.