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A Study to Determine the Safety and Efficacy of the RSV F Vaccine to Protect Infants Via Maternal Immunization

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ClinicalTrials.gov Identifier: NCT02624947
Recruitment Status : Active, not recruiting
First Posted : December 9, 2015
Last Update Posted : June 12, 2018
Sponsor:
Collaborator:
Bill and Melinda Gates Foundation
Information provided by (Responsible Party):
Novavax

Brief Summary:
The purpose of this study is to determine the efficacy of maternal immunization with the RSV F vaccine against symptomatic RSV lower respiratory tract infection (LRTI) with hypoxemia through the first 90 days of life in infants.

Condition or disease Intervention/treatment Phase
Respiratory Syncytial Virus Infections Biological: RSV F vaccine with adjuvant Biological: Formulation buffer Phase 3

Detailed Description:

This is a randomized, observer-blind, placebo-controlled group-sequential design trial enrolling third-trimester pregnant women in the Northern and Southern hemispheres, for up to four consecutive RSV seasons in each hemisphere. The trial is projected to enroll an estimated maximum of 8,618 third-trimester pregnant subjects, but numbers may be smaller based on the operation of the group-sequential design, the incidence rate of the primary clinical endpoint events, and the efficacy of the intervention. Women in the third trimester of a singleton uncomplicated pregnancy and 18 to 40 years of age (inclusive) will be enrolled and randomized in a 1:1 ratio into one of two treatment groups, active or placebo, over approximately the three months prior to peak RSV season. After the first global season of enrollment, the randomization scheme will be changes to a 2:1 (active/placebo) ratio to enable more efficient accrual of the safety database.

All maternal subjects will 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 will span approximately nine (9) months from the first dose, ending six (6) months post-delivery. Study follow-up for infant subjects who are consented will span approximately one (1) year post-delivery.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 8618 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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 Start Date : December 2015
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Treatment Group A
Formulation buffer (0.5mL injection)
Biological: Formulation buffer
Active Comparator: Treatment Group
RSV F vaccine with adjuvant (0.5mL injection)
Biological: RSV F vaccine with adjuvant



Primary Outcome Measures :
  1. Incidence of RSV LRTI with hypoxemia (SpO2 <95% at sea level or <92% at altitudes >1800 meters) in infants through 90 days of life. [ Time Frame: Delivery to 90 days after delivery ]

Secondary Outcome Measures :
  1. Incidence of RSV LRTI with severe hypoxemia (Sp02 <92% at sea level or <87% at altitudes >1800 meters) or the need of high flow nasal cannula or mechanical ventilatory support in infants through 90 days of life [ Time Frame: Delivery to 90 days after delivery ]
  2. Incidence of RSV LRTI with hospitalization in infants through 90 days of life [ Time Frame: Delivery to 90 days after delivery ]
  3. Incidence of RSV LRTI resulting in death in infants through 90 days of life [ Time Frame: Delivery to 90 days after delivery ]
  4. Incidence of RSV LRTI (all severities) in infants through 90 days of life [ Time Frame: Delivery to 90 days after delivery ]
  5. Incidence of healthcare interventions associated with wheezing over the first year of life [ Time Frame: Delivery to 364 days after delivery ]
  6. RSV F protein antibody expressed as ELISA Units [ Time Frame: Day 0 to 180 days after delivery ]
    Geometric Mean Concentrations as EU (GMEU) Geometric Mean Ratio (GMFR) Seroresponse Rate (SRR)

  7. Palivizumab-competitive antibody (PCA) expressed as ug/mL as detected in a competitive ELISA [ Time Frame: Day 0 to 180 days after delivery ]
    Geometric Mean Concentrations as EU (GMEU) Geometric Mean Fold Rise (GMFR)

  8. Neutralizing antibody titer to at least one RSV/A and one RSV/B virus strain. [ Time Frame: Delivery to 90 days after delivery ]
    Geometric Mean Titer (GMT) Geometric Mean Ratio (GMR)

  9. Counts and percentages of term, healthy infants , APGAR scores, length, birth weight, frontal-occipital head circumference (FOC), and physical examination. [ Time Frame: Delivery ]
  10. Counts and percentages of infants with adverse events and serious adverse events during the neonatal period and through the first year of life. [ Time Frame: Delivery to 364 days after delivery ]
  11. Counts and percentages of infants with developmental delay. [ Time Frame: Day 180 to Day 364 after delivery ]
  12. Counts and percentages of maternal subjects with solicited injection site and systemic reactogenicity within seven days of vaccination [ Time Frame: Day 0 to Day 7 ]
  13. Counts and percentages of maternal subjects with unsolicited adverse events, medically-attended adverse events (MAEs), significant new medical conditions (SNMCs) and serious adverse events (SAEs) [ Time Frame: Delivery to 180 days after delivery ]
  14. Clinical safety laboratory assessments of select serum chemistry and hematology parameters [ Time Frame: Day 0 to Delivery ]
  15. Counts and percentages of subjects with Caesarean, vaginal, or instrument assisted vaginal modes of delivery [ Time Frame: Delivery ]
  16. Counts and percentages of maternal subjects with post-immunization onset of specific complications of third-trimester pregnancy and delivery [ Time Frame: Day 0 to Delivery ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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 should 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 estable 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02624947


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Locations
United States, Alabama
Research Site US115
Birmingham, Alabama, United States, 35233
Research Site US035
Cullman, Alabama, United States, 35058
United States, Arizona
Research Site US130
Fort Defiance, Arizona, United States, 86504
Research Site US123
Phoenix, Arizona, United States, 85004
Research Site US103
Tucson, Arizona, United States, 85712
Research Site US129
Whiteriver, Arizona, United States, 85941
United States, California
Research Site US092
Colton, California, United States, 92324
Research Site US114
Huntington Park, California, United States, 90255
Research Site US127
Los Angeles, California, United States, 90057
Research Site US091
Madera, California, United States, 93637
Research Site US093
Riverside, California, United States, 94201
United States, Colorado
Research Site US036
Denver, Colorado, United States, 80204
United States, District of Columbia
Research Site US040
Washington, District of Columbia, United States, 20010
United States, Idaho
Research Site US037
Blackfoot, Idaho, United States, 83221
Research Site US119
Idaho Falls, Idaho, United States, 83404
Research Site US032
Nampa, Idaho, United States, 83687
United States, Illinois
Research Site US095
Chicago, Illinois, United States, 60611
United States, Iowa
Research Site US090
West Des Moines, Iowa, United States, 50266
United States, Kansas
Research Site US038
Augusta, Kansas, United States, 67010
Research Site US031
Hutchinson, Kansas, United States, 67502
United States, Kentucky
Research Site US096
Louisville, Kentucky, United States, 40202
United States, Louisiana
Research Site US126
Alexandria, Louisiana, United States, 71301
Research Site US039
Metairie, Louisiana, United States, 70006
United States, Michigan
Research Site US101
Detroit, Michigan, United States, 48235
United States, Mississippi
Research Site US098
Biloxi, Mississippi, United States, 39531
United States, Nebraska
Research Site US102
Lincoln, Nebraska, United States, 68516
Research Site US025
Norfolk, Nebraska, United States, 68701
United States, New Jersey
Research Site US088
Neptune, New Jersey, United States, 07753
United States, New Mexico
Research Site US131
Gallup, New Mexico, United States, 87301
United States, New York
Research Site US087
Johnson City, New York, United States, 13790
Research Site US086
Syracuse, New York, United States, 13210
United States, North Carolina
Research Site US020
Durham, North Carolina, United States, 27710
Research Site US097
Fort Bragg, North Carolina, United States, 28310
United States, Ohio
Research Site US089
Englewood, Ohio, United States, 45322
United States, Pennsylvania
Research Site US021
Pittsburgh, Pennsylvania, United States, 15213
United States, Texas
Research Site US116
Beaumont, Texas, United States, 77702
Research Site US083
Fort Worth, Texas, United States, 77555
Research Site US043
Galveston, Texas, United States, 77555
Research Site US019
Houston, Texas, United States, 77030
Research Site US128
Houston, Texas, United States, 77036
Research Site US125
Lampasas, Texas, United States, 76550
Research Site US094
Longview, Texas, United States, 75605
Research Site US042
San Antonio, Texas, United States, 78229
United States, Utah
Research Site US121
Salt Lake City, Utah, United States, 84107
Research Site US008
Salt Lake City, Utah, United States, 84124
Research Site US099
Salt Lake City, Utah, United States, 84132
United States, Virginia
Research Site US100
Richmond, Virginia, United States, 23220
United States, Washington
Research Site US041
Seattle, Washington, United States, 98105
Argentina
Research Site AR002
Buenos Aires, Argentina, C1426BOR
Research Site AR006
Cordoba, Argentina, 5000
Research Site AR011
Mendoza, Argentina, 5500
Research Site AR008
Salta, Argentina, 4400
Research Site AR003
Tucuman, Argentina, 4000
Australia, Queensland
Research Site AU010
Brisbane, Queensland, Australia, 4101
Australia, South Australia
Research Site AU007
Adelaide, South Australia, Australia, 5006
Australia, Victoria
Research Site AU011
Clayton, Victoria, Australia, 3148
Research Site AU008
Melbourne, Victoria, Australia, 3010
Australia, Western Australia
Research Site AU009
Perth, Western Australia, Australia, 6008
Bangladesh
Research Site BD001
Sylhet, Sylhet Division, Bangladesh, 3100
Chile
Research Site CL001
Santiago, Region Metropolitana (RM), Chile, 8360160
Research Site CL003
Concepcion, VIII Region, Chile, 4070038
Research Site CL002
Osorno, X Region, Chile, 5311523
Mexico
Research Site MX001
Monterrey, Nuevo Leon, Mexico, 64460
New Zealand
Research Site NZ003
Grafton, Auckland, New Zealand, 1010
Research Site NZ001
Papatoetoe, Aukland, New Zealand, 2025
Research Site NZ002
Christchurch, New Zealand, 8140
Research Site NZ004
Wellington, New Zealand, 6021
Philippines
Research Site PH001
Alabang, Manila, Philippines, 1781
Research Site PH002
Muntinlupa, Metro Manila, Philippines, 1781
South Africa
Research Site ZA004
Parow, Cape Town, South Africa, 7505
Research Site ZA003
Hillbrow, Johannesburg, South Africa, 2001
Research Site ZA007
Thabazimbi, Limpopo Providence, South Africa, 0380
Research Site ZA010
Bellville, Western Cape, South Africa, 7553
Research Site ZA009
Paarl, Western Cape, South Africa, 7646
Research Site ZA011
Worcester, Western Cape, South Africa, 6850
Research Site ZA006
Benoni, South Africa, 1500
Research Site ZA008
Bloemfontein, South Africa, 9301
Research Site ZA002
Soshanguve, South Africa, 0152
Research Site ZA001
Soweto, South Africa, 2013
Spain
Research Site ES002
Barcelona, Spain, 08035
Research Site ES003
Madrid, Spain, 28046
Research Site ES004
Santiago de Compostela, Spain, 15706
Research Site ES001
Sevilla, Spain, 41012
United Kingdom
Research Site UK004
Bristol, United Kingdom, BS2 8EG
Research Site UK001
London, United Kingdom, SW17 0RE
Research Site UK002
Oxford, United Kingdom, OX3 7LE
Research Site UK003
Southampton, United Kingdom, SO16 6YD
Sponsors and Collaborators
Novavax
Bill and Melinda Gates Foundation
Investigators
Study Director: D Nigel Thomas, PhD Novavax Inc

Additional Information:
Responsible Party: Novavax
ClinicalTrials.gov Identifier: NCT02624947     History of Changes
Other Study ID Numbers: RSV-M-301
First Posted: December 9, 2015    Key Record Dates
Last Update Posted: June 12, 2018
Last Verified: June 2018

Keywords provided by Novavax:
RSV

Additional relevant MeSH terms:
Virus Diseases
Respiratory Syncytial Virus Infections
Pneumovirus Infections
Paramyxoviridae Infections
Mononegavirales Infections
RNA Virus Infections
Vaccines
Immunologic Factors
Physiological Effects of Drugs