Immunogenicity and Safety Study of GlaxoSmithKline (GSK) Biologicals' Boostrix™ Vaccine in Pregnant Women

Study Overview
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Brief Summary
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The purpose of this study is to assess the immunogenicity and safety of Boostrix™ when compared to a placebo given during 27-36 weeks of gestation in healthy women aged 18-45 years. Infants born to mothers enrolled in this study will be followed-up in two separate clinical studies: 201330 [DTPA (BOOSTRIX)-048 PRI] and 201334 [DTPA (BOOSTRIX)-049 BST: 048].

Detailed Description
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The protocol was amended to include Spain in the study. The reasons for the Spain-specific amendment are listed below: Based on the feedback from the Spanish Ethics Committee, the evaluation related to the acceptance of cocooning was added in the protocol. The objectives and endpoints to include cocooning were added in the protocol. The eligibility criteria for participation of household contacts were defined in the protocol. The study procedures for household contacts were included.

Official Title
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Immunogenicity and Safety Study of GSK Biologicals' dTpa Vaccine, Boostrix™ (263855) in Pregnant Women

Conditions
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Diphtheria-Tetanus-acellular Pertussis Vaccines

Intervention / Treatment
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* Biological: Boostrix™
* Drug: Saline placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for study subjects: Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol. Written informed consent obtained from the subject prior to performing any study specific procedure, as per local regulations. A healthy pregnant woman between, and including, 18 and 45 years of age at the time of screening. Pregnant subjects at 27 0/7-36 6/7 weeks (completed 27 weeks but not 37 weeks) of gestation at the time of vaccination (Visit 1), as established by ultrasound examination. Not at high risk for complications, as determined by the obstetrical algorithm for identification of eligible subjects and the Obstetrical Risk Assessment Form. No significant foetal abnormalities, as observed by the level II ultrasound testing conducted after 18 weeks of gestation. Nuchal translucency scan, serum testing and any other prenatal tests, if conducted, should suggest normal pregnancy. Willing to have the infant born immunised with Infanrix hexa and Prevenar 13, as per national recommendations, in the follow-up clinical studies DTPA (BOOSTRIX)-048 PRI and DTPA (BOOSTRIX)-049 BST: 048. Subjects who do not plan to give their child for adoption or place the child in care. Inclusion criteria for household contacts in Spain: Household contacts living in the same house as that of the infant. Household contacts or parent(s)/LAR(s) of the household contacts who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. reporting of SAEs). Written informed consent obtained from the household contacts or the parent(s)/LAR(s) prior to vaccination, as per local regulations. Household contacts who are eligible to receive a booster dose of DTP-containing vaccine according to the Summary of Product Characteristics (SmPC) of Boostrix and according to the local governmental recommendations in Spain. Female household contacts of non-childbearing potential may be enrolled in the study. - Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy or post-menopause. Female household contacts of childbearing potential may be enrolled in the study , if the household contact has practiced adequate contraception for 30 days prior to vaccination, has a negative pregnancy test on the day of vaccination and has agreed to continue adequate contraception for 2 months after receiving the vaccine dose. Exclusion Criteria for study subjects: Subjects diagnosed with multiple pregnancies (twins, triplets etc.). Previous vaccination containing diphtheria, tetanus or pertussis antigens or diphtheria and tetanus toxoids at any time during the current pregnancy. Women with co-morbid medical or obstetric conditions that in the opinion of the investigator have the potential to complicate the pregnancy course and outcomes. Gestational diabetes as determined by glucose tolerance test conducted after 20 weeks of gestation, as per local recommendations of the country. History of early onset (<34 weeks of gestation) of eclampsia/pre-eclampsia in previous pregnancy. History of major congenital anomalies in previous pregnancies. Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine anytime during the current pregnancy or planned use during the study period. Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe. Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine. For corticosteroids, this will mean prednisone ≥20 mg/day, or equivalent. Inhaled and topical steroids are allowed. Administration of long-acting immune-modifying drugs at any time during the study period. Planned administration/administration of a vaccine not foreseen by the study protocol in the period within the period starting 30 days before and 30 days after the dose of vaccine with the exception of seasonal influenza vaccine that can be administered anytime during the study period. Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product (pharmaceutical product or device). Serious underlying medical condition [e.g., immunosuppressive disease or therapy, human immunodeficiency virus infection, collagen vascular disease, epilepsy, diabetes mellitus, chronic hypertension, moderate to severe asthma, lung/heart disease, liver/kidney disease, infections including TORCHES (toxoplasmosis, rubella, cytomegalovirus, herpes simplex, syphilis) infections]. History of an encephalopathy of unknown aetiology, occurring within 7 days following previous vaccination with pertussis-containing vaccine. History of transient thrombocytopenia or neurological complications (for convulsions or hypotonic-hyporesponsive episodes) following an earlier immunisation against diphtheria and/or tetanus Significant mental illness (e.g. schizophrenia, psychosis and major depression). Family history (first degree relatives only) of congenital anomalies, recurrent pregnancy losses (two or more consecutive losses) and unexplained neonatal death(s) in the subject. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine. History of febrile illness within the past 72 hours. History of physician-diagnosed or laboratory-confirmed pertussis within the past five years. Anything that would prevent subject from completing the study or put the subject at risk, as determined by the investigator. Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 37.5°C /99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C /100.4°F on rectal route. Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator. Administration of immunoglobulins and/or any blood products within the 3 months preceding the dose of study vaccine, or planned administration during the study period, with the exception of anti-D (Rh)-immunoglobulin. History of chronic excessive alcohol consumption and/or drug abuse. Exclusion criteria for household contacts in Spain: Child in care. Concurrently participating in another clinical study, at any time during the study period, in which the household contact has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the dose of study vaccine, or planned use during the study period. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine. History of an encephalopathy of unknown aetiology, occurring within 7 days following previous vaccination with pertussis-containing vaccine. Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 37.5°C /99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C /100.4°F on rectal route. The preferred route of recording temperature will be axillary in household contacts. Household contacts with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator. Anything that would put the household contact at risk, as determined by the investigator. Pregnant or lactating household contacts. Household contacts planning to become pregnant or planning to discontinue contraceptive precautions prior to 2 months post-vaccination.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dTpa Group<br>This group will consist of pregnant women who will receive a single dose of Boostrix™ at 27-36 weeks (i.e. completed 27 weeks until 36 weeks) of gestation (Visit 1) and will receive a dose of the placebo post-delivery (within 72 hours). | Biological: Boostrix™<br>* One dose administered intramuscularly in the deltoid muscle of the non-dominant arm.<br>Drug: Saline placebo<br>* One dose administered intramuscularly in the deltoid muscle of the non-dominant arm.<br>|
| Placebo Comparator: Control Group<br>This group will consist of pregnant women who will receive a single dose of placebo at 27-36 weeks (i.e. completed 27 weeks until 36 weeks) of gestation (Visit 1) and will receive a dose of Boostrix™ post-delivery (within 72 hours). | Biological: Boostrix™<br>* One dose administered intramuscularly in the deltoid muscle of the non-dominant arm.<br>Drug: Saline placebo<br>* One dose administered intramuscularly in the deltoid muscle of the non-dominant arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibody Concentrations Against Pertussis Toxoid Antigen (Anti-PT), Filamentous Haemagglutinin Antigen (Anti-FHA) and Pertactin Antigen (Anti-PRN) in Cord Blood Samples | Antibody concentrations were assessed by Enzyme-linked immunosorbent assay (ELISA), tabulated as Geometric Mean Concentrations (GMCs) and expressed in International units per mililiter (IU/mL) for the following assay cut-offs: 2.693 IU/mL for anti-PT, 2.046 IU/mL for anti-FHA and 2.187 IU/mL for anti-PRN. | At delivery - Visit 3 (anytime after 28 weeks of gestation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects by Pregnancy Outcomes | Pregnancy outcomes included live birth with no congenital anomalies, live birth with congenital anomalies, still birth with no congenital anomalies, still birth with congenital anomalies, elective termination with no congenital anomalies and elective termination with congenital anomalies. No subjects with still birth or elective termination of infant were reported. | From Day 0 (Visit 1) to Month 2 (Visit 4, end of the study). | 
| Percentage of Subjects With Listed Pregnancy/Neonate Related Adverse Events of Interest | Listed pregnancy-related adverse events of interest/ neonate-related events of interest included gestational diabetes, pregnancy-related hypertension, premature rupture of mem-branes, preterm premature rupture of membranes, premature labour, premature uterine contractions, intrauterine growth restriction/poor foetal growth, pre-eclampsia, eclampsia, vaginal or intrauterine haemorrhage, maternal death, preterm birth, neonatal death, small for gestational age, neonatal hypoxic ischaemic encephalopathy and failure to thrive/growth deficiency were reported. | From Day 0 (Visit 1) to Month 2 post-delivery (Visit 4, end of the study). | 
| Percentage of Seroprotected Subjects Against Diphteria Antigen (Anti-D), Tetanus Antigen (Anti-T) and of Seropositive Subjects Against Anti-PT, Anti-FHA and Anti-PRN | A seroprotected subject against diphteria and tetanus was a subject with antibody concentration ≥ 0.1 IU/mL. A seropositive subject was a subjects with antibody concentration ≥ 2.693 IU/mL for anti-PT, ≥ 2.046 IU/mL for anti-FHA and ≥ 2.187 IU/mL for anti-PRN. | One month post vaccination (Day 30) during pregnancy | 
| Anti-D, Anti-T, Anti-PT, Anti-FHA and Anti-PRN Antibody Concentrations | Antibody concentrations were determined by ELISA, tabulated as GMCs and expressed in IU/mL. | One month post vaccination (Day 30) during pregnancy | 
| Percentage of Subjects With Vaccine Response to Anti-D and Anti-T | Vaccine response for anti-D and anti-T was defined as: for initially seronegative subjects (S-) with pre-vaccination concentration below cut-off: < 0.1 IU/mL) was an antibody concentration at least four times the assay cut-off (post-vaccination concentration ≥ 0.4 IU/mL); for initially seropositive subjects (S+) with pre-vaccination concentration ≥ 0.1 IU/mL): an increase in antibody concentrations of at least four times the pre-vaccination concentration. | One month post vaccination (Day 30) during pregnancy | 
| Percentage of Subjects With Vaccine Response to Anti-PT, Anti-FHA and Anti-PRN | Vaccine response to PT, FHA and PRN antigens is defined as: for subjects with pre-vaccination antibody concentration below the assay cut-off (S-), post-vaccination anti-body concentration ≥ 4 times the assay cut-off; for subjects with pre-vaccination antibody concentration between the assay cut-off and below 4 times the assay cut-off (S+), post-vaccination antibody concentration ≥ 4 times the pre-vaccination antibody concentration, and for subjects with pre-vaccination antibody concentration ≥4 times the assay cut-off (S+), post-vaccination antibody concentration ≥2 times the pre-vaccination antibody concentration. | One month post vaccination (Day 30) during pregnancy | 
| Percentage of Seropositive Subjects Against Anti-PT, Anti-FHA and Anti-PRN in the Cord Blood Samples | For this assay the anti-PT, anti-FHA and anti-PRN seropositivity status was determined from the cord blood samples. The seropositivity cut-offs were the following: 2.693 IU/mL for anti-PT, 2.046 IU/mL for anti-FHA and 2.187 IU/mL for anti-PRN. | At delivery - Visit 3 (anytime after 27 eligible weeks of gestation) | 
| Percentage of Subjects With Solicited Local Adverse Events (AEs) | Assessed solicited local symptoms were pain, redness and swelling. Any = any report of the specified symptom irrespective of intensity grade. Dose 1 = pregnancy dose at Day 0 - Visit 1, Dose 2 = post-delivery dose at birth - Visit 3. | During the 8-day (Day 0-Day 7) follow-up period after vaccination during pregnancy | 
| Percentage of Subjects With Solicited General AEs | Assessed solicited general symptoms were fatigue, gastrointestinal symptoms (nausea, vomiting, diarrhoea and/or abdominal pain), headache and fever [defined as oral, axillary or tympanic temperature ≥ 37.5 degrees Celsius (°C) or rectal temperature ≥ 38.0 °C]. Any = any report of the specified symptom irrespective of intensity grade. Dose 1 = pregnancy dose at Day 0 - Visit 1, Dose 2 = post-delivery dose at birth - Visit 3. | During the 8-day (Day 0-Day 7) follow-up period after vaccination during pregnancy | 
| Percentage of Subjects With Unsolicited AEs | An unsolicited AE was any AE that was not solicited using a subject diary and that was spontaneously communicated by the subject. Also any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event. Dose 1 = pregnancy dose at Day 0 - Visit 1, Dose 2 = post-delivery dose at birth - Visit 3. | Within 31 days (Day 0 - Day 30) after each vaccination | 
| Percentage of Infants With Unsolicited AEs | An unsolicited AE was any AE that was not solicited using a subject diary and that was spontaneously communicated by the subject. Also any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event. | From delivery to Month 2 post delivery (Visit 4, end of the study). | 
| Number of Subjects With Serious AEs (SAEs) | A SAE was any untoward medical occurrence that resulted in death, was life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or a congenital anomaly/birth defect in the offspring of a study subject. | From Day 0 (Visit 1) to Month 2 (Visit 4, end of the study). | 
| Percentage of Household Contacts of the Infants Born to Pregnant Women Vaccinated in Spain | This analysis assessed the vaccination status of the household contacts (who accepted, received or refused vaccination) and also the reasons for refusal (not coming to site, refused to be vaccinated, unspecified) as part of an assessment of cocooning among the eligible household contacts. | From Day 0 (Visit 1) to Month 2 (Visit 4, end of the study). | 
| Percentage of Household Contacts With SAEs | SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects. | During the 31-day (Days 0-30) follow-up period post-vaccination (Boostrix administered preferably 2 weeks before the birth of the infant, Visit 3). |