Study on the Safety and Immunogenicity of Boostrix Vaccine in Pregnant Malian Women and Their Infants

Study Overview
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Brief Summary
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This is a phase II, randomized, double-blind, active-controlled study to evaluate the safety, immunogenicity, and effect on infant immune responses of a single dose of Tetanus diphtheria acellular pertussis vaccine (Tdap) in pregnant women in Mali. 200 healthy pregnant women, ages 18 through 39 years, inclusive, who meet all eligibility criteria will be randomly allocated in a 2:1 ratio to receive either Tdap (BOOSTRIX) or Tetanus diphtheria toxoid (Td) at 14 0/7 weeks through 26 6/7 weeks estimated Gestational Age (GA). For the fetuses of pregnant subjects, GA will be established by ultrasound, whenever possible, in combination with date of last menstrual period (LMP), when available, and fundal height. Study duration is 21 months: approximately 2 months in the start-up period, 6 months enrolling subjects, and 13 months (3-7 months while pregnant and 6 months postpartum) from last subject vaccinated until she and her infant complete follow-up. The primary objectives of this study are: 1) to assess the safety and tolerability of a single 0.5 mL intramuscular injection of BOOSTRIX in pregnant women; 2) to assess the safety of a single maternal BOOSTRIX vaccination on the fetus and infant; 3) to assess the level of Pertussis Toxin (PT) antibody at birth among infants whose mothers received a single dose of BOOSTRIX or Td while pregnant.

Detailed Description
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This is a phase II, randomized, double-blind, active-controlled study to evaluate the safety, immunogenicity, and effect on infant immune responses of a single dose of Tetanus diphtheria acellular pertussis vaccine (Tdap) in pregnant women in Mali. 200 healthy pregnant women, ages 18 through 39 years, inclusive, who meet all eligibility criteria will be randomly allocated in a 2:1 ratio to receive either Tdap (BOOSTRIX) or Tetanus diphtheria toxoid (Td) at 14 0/7 weeks through 26 6/7 weeks estimated Gestational Age (GA). For the fetuses of pregnant subjects, GA will be established by ultrasound, whenever possible, in combination with date of last menstrual period (LMP), when available, and fundal height. Study duration is 21 months: approximately 2 months in the start-up period, 6 months enrolling subjects, and 13 months (3-7 months while pregnant and 6 months postpartum) from last subject vaccinated until she and her infant complete follow-up. The primary objectives of this study are: 1) to assess the safety and tolerability of a single 0.5 mL intramuscular injection of BOOSTRIX in pregnant women; 2) to assess the safety of a single maternal BOOSTRIX vaccination on the fetus and infant; 3) to assess the level of Pertussis Toxin (PT) antibody at birth among infants whose mothers received a single dose of BOOSTRIX or Td while pregnant. The secondary objectives are: 1) to assess the antibody response to BOOSTRIX vaccine antigens in pregnant women one month after receipt of BOOSTRIX, at the time of delivery, and at 6 months after delivery; 2) to compare the antibody levels of BOOSTRIX vaccine antigens at birth (cord blood) and 6 weeks of age (before receiving any infant doses of Diphtheria, Tetanus, and whole-cell Pertussis (DTwP)) in infants whose mothers received BOOSTRIX or Td during pregnancy; 3) to assess placental antibody transfer by determining the ratio of maternal and infant BOOSTRIX -specific antibody responses at delivery; 4) to assess interference with infant antibody responses to DTwP either prior to the second dose of the primary DTwP series, at approximately 10 weeks of age (in 1/2 of subjects), or approximately one month after the third dose of the primary DTwP series, at approximately 18 weeks of age (in 1/2 of subjects), and at 6 months of age (all subjects).

Official Title
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A Phase II Double-Blind Trial to Evaluate the Safety, Immunogenicity and Effect on Infant Immune Responses of a Single Dose of Tdap in Pregnant Women in Mali

Conditions
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Clostridium Difficile Immunisation, Diphtheria, Diphtheria Immunisation, Pertussis, Tetanus, Tetanus Immunisation

Intervention / Treatment
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* Biological: Tetanus and Diphtheria Toxoids Adsorbed
* Biological: Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed onto aluminum hydroxide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy pregnant woman 18-39 years of age, inclusive. Singleton fetus, with estimated gestational age of 14 0/7 through 26 6/7 weeks gestation, inclusive, on the day of study vaccination. Provide written consent after the nature of the study has been explained according to local regulatory requirements and prior to any study procedures*. *Prior to obtaining individual informed consent for each subject, the investigators will obtain community consent by discussing the trial with all the appropriate local groups, as necessary, to obtain permission to approach the subjects. Written, informed consent for participation in the trial will be obtained by the investigators from all individual subjects. The consent forms will be written in French, the official language of Mali, and will be translated into Bambara, the most prevalent of the local languages, and recorded on audiotape. In good health as determined by medical history, targeted physical examination* (physical examination performed as part of routine antenatal care of a study-specific brief exam may be used to determine eligibility), vital signs (oral temperature < 37.8 degrees Celsius; pulse 55 to 100 beats per minute (bpm), inclusive; systolic blood pressure 90 to 140 millimeters of mercury (mm Hg), inclusive; diastolic blood pressure 55 to 90 mm Hg, inclusive), and clinical judgment of the investigator. *If indicated based on medical history, to evaluate acute or currently ongoing chronic medical diagnoses or conditions that would affect the assessment of eligibility and safety of subjects. Chronic medical diagnoses or conditions being actively managed must be within acceptable limits in the last 180 days. Any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the site principal investigator or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition. Similarly, medication changes subsequent to enrollment and the study vaccination are acceptable provided the subject is asymptomatic, condition stable, and there is no additional risk to the subject or interference with the evaluation of responses to the study vaccination. Ability to comprehend and comply with all study procedures, as determined by the investigator determining eligibility, and availability for follow-up. Willing to allow study staff to gather pertinent medical information, including pregnancy outcome data and medical information about her infant. Exclusion Criteria: History of illness or an ongoing illness that, in the opinion of the investigator, may pose additional risk to the subject or her fetus if she participates in the study. Infection requiring systemic antibiotics or antiviral treatment within the 7 days prior to study vaccination. Fever (oral temperature > / = 37.8 degrees Celsius/100.0 degrees Fahrenheit) or other acute illness within 3 days prior to study vaccination*. *An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site principal investigator or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol. Known active neoplastic disease (excluding non-melanoma skin cancer), anticancer chemotherapy, or radiation therapy (cytotoxic) within 3 years prior to study vaccination. History of any hematologic malignancy at any time. A history of a serious adverse event following previous immunizations (e.g., Bell's Palsy, Guillain-Barre Syndrome, encephalopathy), or history of progressive neurologic disorders. Known or suspected disease that impairs the immune system including known or suspected HIV infection or HIV-related disease. Receipt of immunosuppressive therapy, including long-term use of glucocorticoids: oral, inhaled, intranasal or parenteral prednisone > / = 20 mg/day or equivalent for more than 2 weeks within the 30 days prior to enrollment. Use of topical corticosteroids is allowed. Known hepatitis B or hepatitis C infection, by history or medical record. Behavioral or cognitive impairment or psychiatric disease (includes hospitalization for psychiatric illness, suicide attempt, or confinement for danger to self or others within 10 years prior to study vaccination) that, in the opinion of the investigator, may interfere with the subject's ability to participate in the trial. Have a history of alcohol or drug abuse within 5 years prior to study vaccination (that is believed by the site investigator to potentially interfere with the subject's ability to participate in the study). Known hypersensitivity or allergy to any component of the study vaccine (formaldehyde, alum). History of severe allergic reaction (e.g., anaphylaxis) after a previous dose of BOOSTRIX or any other vaccine directed against tetanus, diphtheria, or pertussis. Receipt or planned receipt of any live licensed vaccine within 30 days before or after vaccination or any inactivated licensed vaccine within 14 days before or after vaccination. Receipt of immunoglobulin (except RhoGAM, which is allowed) or other blood products within 90 days prior to study vaccination. Receipt of an experimental agent or device within 30 days prior to vaccination, or the expected receipt of an experimental agent* (other than BOOSTRIX) during this trial-reporting period. *Experimental agents include vaccines, drugs, biologics, devices, blood products, and medications. Subjects who have received a licensed product, as a subject in a clinical trial, within 30 days prior to vaccination or who are expecting to enroll in such a trial during the study period will also be excluded. Observational studies, surveys, and other studies that do not involve experimental agents or devices are allowed. High risk for serious obstetrical complication (refer to ACOG Practice Bulletins for definitions, as necessary)*. *Including the following: (a) gestational hypertension (well controlled history of essential or gestational hypertension, as evidenced by normal BPs as defined above, is allowed), (b) gestational diabetes not controlled by diet and exercise (the use of insulin or glyburide to control gDM, at the time of enrollment, is exclusionary), (c) current pre-eclampsia or eclampsia, (d) known current multiple gestation, (e)history of preterm delivery before EGA 35 weeks 0 days or current preterm labor, and/or (f) known intrauterine fetal growth restriction (defined as ultrasound confirmation of an estimated fetal weight that is less than the 10th percentile for gestational age). Pregnant with a fetus with a known or suspected major congenital anomaly or genetic abnormality. Study personnel or immediate family members (brother, sister, child, parent) or the spouse of study personnel.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>0.5 ml single dose of Tdap (Tetanus, Diphtheria, Acellular Pertussis Vaccine), BOOSTRIX administered intramuscularly to pregnant women at 14 0/7 weeks through 26 6/7 weeks estimated Gestational Age (GA). N=133 | Biological: Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed onto aluminum hydroxide<br>* A sterile isotonic suspension of tetanus and diphtheria toxoids and pertussis antigens adsorbed on Aluminum hydroxide.<br>|
| Active Comparator: Group 2<br>0.5 ml single dose of Td (Tetanus, Diphtheria Toxoid) administered intramuscularly to pregnant women at 14 0/7 weeks through 26 6/7 weeks estimated GA. N=67 | Biological: Tetanus and Diphtheria Toxoids Adsorbed<br>* Used for active immunization of adults and children 7 years of age and older against diphtheria and tetanus.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Pregnant Women Reporting Related Serious Adverse Events (SAEs) and Unrelated SAEs | SAEs included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation or a congenital anomaly/birth defect. All SAEs were reported from time of first study vaccination through approximately 6 months after the first study vaccination | Study Day 1 through Day 180 (6-months post-partum) | 
| Number of Pregnant Women Reporting Pregnancy-Specific Adverse Events (AEs) | Pregnancy related AEs include: pregnancy loss (graded as severe [grade 3] if occurred), bleeding during pregnancy prior to the onset of labor, postpartum hemorrhage, postabortal endometritis/salpingitis, preterm rupture of membranes, preterm contractions/labor/delivery, poor fetal growth, hypertension, preeclampsia/eclampsia, chorioamnionitis, postpartum endometriosis, gestational diabetes mellitus, and/or pregnancy-related clinical AE not previously identified in this list. | Study Day 1 through Day 180 (6-months post-partum) | 
| Number of Infants Reporting Related SAEs and Unrelated SAEs | SAEs included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation or a congenital anomaly/birth defect. All SAEs were reported from time of birth through 6 months of age. | Birth Day through 6 months of age | 
| Number of Infants Reporting Pregnancy-specific AEs | Infant pregnant related AEs include: preterm birth, low birth weight, neonatal complications in a term infant, congenital anomalies/birth defects, and/or clinical AE in the newborn not identified previously in this list. | Birth Day through 6 months of age | 
| Number of Pregnant Women Reporting Solicited Injection Site and Systemic Reactogenicity Events | Local AEs solicited on a memory aid provided to participants included Pain, Tenderness, Ecchymosis (functional grade based on interference with daily activities), Ecchymosis (any measured value >0mm), Erythema (functional grade), Erythema (any measured value >0mm), Induration (functional grade), and Induration (any measured value >0mm). Systemic AEs solicited on a memory aid provided to participants included Elevated Oral Temperature, Feverishness, Fatigue, Malaise, Myalgia, Arthralgia, Headache, Allergic reaction, and Nausea. Participants are considered reporting the local or systemic AE if they reported mild or greater severity at any time during the 8 days at or following the first vaccination. | Pre-Dose Day 1, Post-Dose Day 1, Day 4, Day 8 | 
| Number of Pregnant Women Reporting Unsolicited Non-serious AEs | Frequency of all unsolicited non-serious AEs from day of study vaccination (Day 1) to Day 31, compared between those who received BOOSTRIX and those who received Td. | Day 1 through Day 31 | 
| Geometric Mean Concentration (GMC) of Serum IgG Antibodies to Pertussis Toxin (PT) in Infants Born to Women Receiving BOOSTRIX or Td | Geometric Mean Concentration (GMC) of serum IgG antibodies to PT as measured by Enzyme-Linked Immunosorbent Assay (ELISA) at birth between infants born to women vaccinated with BOOSTRIX or Td. DTwP is Diphtheria, Tetanus, and whole cell Pertussis vaccine. | Birth Day, Prior to receipt of first dose of DTwP (approximately 6 weeks of age), One month after receipt of first dose of DTwP (approximately 10 weeks of age), One month after receipt of last dose of DTwP (approximately 18 weeks of age), 6 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GMC of Serum IgG Antibodies to PT in Pregnant Women Receiving BOOSTRIX or Td | GMC of serum IgG antibodies to PT as measured by Enzyme-Linked Immunosorbent Assay (ELISA) between women vaccinated with BOOSTRIX or Td. | Pre-dose Day 1, One month after vaccination, at delivery, Day 180 (approximately 6 months after delivery) | 
| GMC of Serum IgG Antibodies to Filamentous Hemagglutinin (FHA) in Pregnant Women Receiving BOOSTRIX or Td | GMC of serum IgG antibodies to FHA as measured by Enzyme-Linked Immunosorbent Assay (ELISA) between women vaccinated with BOOSTRIX or Td. | Pre-dose Day 1, One month after vaccination, at delivery, Day 180 (approximately 6 months after delivery) | 
| GMC of Serum IgG Antibodies to Pertactin (PRN) in Pregnant Women Receiving BOOSTRIX or Td | GMC of serum IgG antibodies to PRN as measured by Enzyme-Linked Immunosorbent Assay (ELISA) between women vaccinated with BOOSTRIX or Td. | Pre-dose Day 1, One month after vaccination, at delivery, Day 180 (approximately 6 months after delivery) | 
| GMC of Serum IgG Antibodies to Tetanus in Pregnant Women Receiving BOOSTRIX or Td | GMC of serum IgG antibodies to Tetanus as measured by Enzyme-Linked Immunosorbent Assay (ELISA) between women vaccinated with BOOSTRIX or Td. | Pre-dose Day 1, One month after vaccination, at delivery, Day 180 (approximately 6 months after delivery) | 
| GMC of Serum IgG Antibodies to Diphtheria in Pregnant Women Receiving BOOSTRIX or Td | GMC of serum IgG antibodies to Diphtheria as measured by Enzyme-Linked Immunosorbent Assay (ELISA) between women vaccinated with BOOSTRIX or Td. | Pre-dose Day 1, One month after vaccination, at delivery, Day 180 (approximately 6 months after delivery) | 
| GMC of Serum IgG Antibodies to FHA in Infants Born to Women Receiving BOOSTRIX or Td | GMC of serum IgG antibodies to FHA as measured by Enzyme-Linked Immunosorbent Assay (ELISA) at birth between infants born to women vaccinated with BOOSTRIX or Td. | Birth Day, Prior to receipt of first dose of DTwP (approximately 6 weeks of age), One month after receipt of first dose of DTwP (approximately 10 weeks of age), One month after receipt of last dose of DTwP (approximately 18 weeks of age), 6 months of age | 
| GMC of Serum IgG Antibodies to PRN in Infants Born to Women Receiving BOOSTRIX or Td | GMC of serum IgG antibodies to PRN as measured by Enzyme-Linked Immunosorbent Assay (ELISA) at birth between infants born to women vaccinated with BOOSTRIX or Td. | Birth Day, Prior to receipt of first dose of DTwP (approximately 6 weeks of age), One month after receipt of first dose of DTwP (approximately 10 weeks of age), One month after receipt of last dose of DTwP (approximately 18 weeks of age), 6 months of age | 
| GMC of Serum IgG Antibodies to Tetanus in Infants Born to Women Receiving BOOSTRIX or Td | GMC of serum IgG antibodies to Tetanus as measured by Enzyme-Linked Immunosorbent Assay (ELISA) at birth between infants born to women vaccinated with BOOSTRIX or Td. | Birth Day, Prior to receipt of first dose of DTwP (approximately 6 weeks of age), One month after receipt of first dose of DTwP (approximately 10 weeks of age), One month after receipt of last dose of DTwP (approximately 18 weeks of age), 6 months of age | 
| GMC of Serum IgG Antibodies to Diphtheria in Infants Born to Women Receiving BOOSTRIX or Td | GMC of serum IgG antibodies to Diphtheria as measured by Enzyme-Linked Immunosorbent Assay (ELISA) at birth between infants born to women vaccinated with BOOSTRIX or Td. | Birth Day, Prior to receipt of first dose of DTwP (approximately 6 weeks of age), One month after receipt of first dose of DTwP (approximately 10 weeks of age), One month after receipt of last dose of DTwP (approximately 18 weeks of age), 6 months of age | 
| GMC of Serum IgG Antibodies to Fimbriae 2/3 (FIM 2/3) in Infants Born to Women Receiving BOOSTRIX or Td | GMC of serum IgG antibodies to FIM 2/3 as measured by Enzyme-Linked Immunosorbent Assay (ELISA) at birth between infants born to women vaccinated with BOOSTRIX or Td. | Birth Day, Prior to receipt of first dose of DTwP (approximately 6 weeks of age), One month after receipt of first dose of DTwP (approximately 10 weeks of age), One month after receipt of last dose of DTwP (approximately 18 weeks of age), 6 months of age | 
| Geometric Mean Ratio (GMR) of Maternal and Infant-specific Tdap-specific Antibodies | GMR of maternal and infant-specific Tdap-specific antibodies (PT, FHA, PRN, tetanus, diphtheria) as measured by ELISA at delivery/birth after intrapartum receipt of BOOSTRIX versus Td. GMR represents the geometric mean ratio in infant antibody concentration at birth to maternal antibody concentration at delivery. | Time of delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BOOSTRIX, Immunogenicity, Infant, Mali, Phase II, Pregnant Women, Safety, Tdap