E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Respiratory syncytial virus (RSV) is the leading viral cause of severe lower respiratory tract disease in infants and young children worldwide. In industrialized countries, nearly all children have been infected with RSV by 2 years of age. Most infected children present with mild upper respiratory tract symptoms, but a subset develops severe lower respiratory tract disease characterized by tachypnea, hyperinflation, crackles, and expiratory wheezing (i.e., bronchiolitis and pneumonia). |
|
E.1.1.1 | Medical condition in easily understood language |
Lower respiratory tract disease in infants and young children |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061603 |
E.1.2 | Term | Respiratory syncytial virus infection |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the efficacy of maternal immunization with the RSV F vaccine against medically-significant RSV lower respiratory tract infection (LRTI) with EITHER hypoxemia (peripheral oxygen saturation [SpO2] < 95% at sea level or < 92% at altitudes > 1800 meters) OR tachypnea (≥ 70 bpm for infants 0 to 59 days of age or ≥ 60 bpm for infants ≥ 60 days of age) through the first 90 days of life in infants of maternal RSV F vaccinees as compared to placebo recipients. In the event that efficacy is shown through the first 90 days of life, a hierarchical sequence of hypothesis tests will be carried out to examine efficacy at 120, 150, and 180 days of life. |
|
E.2.2 | Secondary objectives of the trial |
To determine the efficacy of maternal immunization with the RSV F vaccine in reducing the incidence of: RSV LRTI with severe hypoxemia (SpO2 < 92% at sea level or < 87% at altitudes > 1800 meters) or the need for high flow nasal cannula or mechanical ventilatory support, RSV LRTI leading to hospitalization, and resulting in death, through the first 90 days of life in infants of maternal RSV F vaccinees as compared to placebo recipients; to determine the efficacy of maternal immunization with the RSV F vaccine in reducing the incidence of all RSV LRTI through the first 90 days of life in infants of maternal RSV F vaccinees as compared to placebo recipients; to determine the efficacy of maternal immunization with the RSV F vaccine in reducing the incidence of healthcare interventions associated with wheezing through the first year of life in infants of maternal RSV F vaccinees as compared to placebo recipients. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) ≥ 18 and ≤ 40 years-of-age (which connotes a lower limit of 18 years and 0 days and an upper limit of 40 years and 0 days).
2) Singleton pregnancy of 28 to 360/7 weeks gestation on the day of planned vaccination. Documentation of gestational age will be based on one of the following composite criteria:
(a) Gestational Age Dating Based on First Trimester Data (data obtained ≤ 136/7 weeks):
(b) Gestational Age Dating Based on Early Second Trimester Data (data obtained 140/7 to 216/7 weeks):
(c) Gestational Age Dating Based on Later Second Trimester Data (data obtained 220/7 to 276/7 weeks)
(d) 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 (≤ 276/7 weeks) will be used to establish the gestational age.
3) Documentation of a second or third (between 180/7 weeks and prior to randomization) trimester ultrasound with no major fetal anomalies identified.
4) Good general maternal health as demonstrated by:
o Medical history (including history of clinically significant adverse reactions to prior vaccines and allergies).
o Physical examination including at least vital signs (blood pressure, pulse, respirations, and axillary body 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).
o Clinical laboratory parameters that include:
o 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 third trimester of pregnancy, specified in the toxicity grading scale (TGS, provided in the Study Operations Manual) and should be referenced to assess for any abnormalities. This testing should be performed by the central laboratory.
o 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. |
|
E.4 | Principal exclusion criteria |
1) Symptomatic cardiac or pulmonary disease requiring chronic drug therapy, including hypertension and asthma. Asthma is exclusionary if the subject is receiving chronic systemic glucocorticoids at any dose or inhaled glucocorticoids at any dose > 500 μg per day of beclomethasone or fluticasone, or > 800 μg 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 (use of low-dose aspirin as prophylaxis [e.g., for the prevention of morbidity and mortality from preeclampsia] is acceptable in 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 ≥ 10 mg 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, including a history of severe post-partumdepression, 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 axillary body temperature > 38.0°C).
30) History of a serious adverse reaction (e.g., anaphylaxis) to any prior vaccine.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint (In Infant Subjects):
• Incidence of medically-significant RSV LRTI, as defined by:
o The presence of RSV infection confirmed by detection of RSV genome by RT-PCR on respiratory secretions (obtained within the continuous illness episode which fulfills the other criteria listed below); AND
o At least one manifestation of lower respiratory tract infection [LRTI] from among the following: cough, nasal flaring, lower chest wall indrawing, subcostal retraction, stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed apnea; AND
o Evidence of medical significance as defined by the presence of:
- EITHER hypoxemia (peripheral oxygen saturation [SpO2] < 95% at sea level or < 92% at altitudes > 1800 meters) OR
- Tachypnea (≥ 70 bpm in infants 0 to 59 days of age and ≥ 60 bpm in infants ≥ 60 days |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
•Incidence of RSV LRTI with severe hypoxemia (SpO2 < 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,
•Incidence of RSV LRTI with hospitalization in infants through 90 days of life,
•Incidence of RSV LRTI resulting in death in infants through 90 days of life,
•Incidence of RSV LRTI (all severities) in infants through 90 days of life.
•Incidence of healthcare interventions associated with wheezing through the first year of life.
A subgroup analysis for all efficacy endpoints will consider all infants of mothers who received test article < 2 weeks prior to delivery and all infants of mothers who received any test article. For all secondary efficacy endpoints, analyses at 120, 150, and 180 days of age will be performed dependent on successful outcomes at the prior, shorter intervals. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Chile |
India |
Mexico |
New Zealand |
Philippines |
South Africa |
Spain |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Last visit of the last subject |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |