A Phase 4, Placebo-Controlled, Randomized Study to Evaluate the Immunogenicity and Safety of HPV and Tdap When Administered With MenACWY in Adolescents

A Phase 4, Placebo-Controlled, Randomized Study to Evaluate the Immunogenicity and Safety of a Combined Tetanus, Reduced Diphtheria Toxoid, Acellular Pertussis Vaccine (Tdap, Boostrix®) and Quadrivalent Human Papillomavirus [Types 6, 11, 16, 18] Recombinant Vaccine (Gardasil®) in Healthy Adolescents When Administered With MenACWY Conjugate Vaccine

The main objective is to determine whether immune responses to Tdap (GlaxoSmithKline, Boostrix®) and HPV vaccine (Merck & Co., Inc., Gardasil®) when administered concomitantly with MenACWY are comparable to responses elicited by these vaccines when given alone.

Study Overview

• Status: Completed
• Conditions: Meningococcal Meningitis
• Intervention / Treatment: Biological: Placebo + Combined Tetanus, Reduced Diphtheria Toxoid, Acellular Pertussis Vaccine + Quadrivalent Human Papillomavirus Vaccine; Biological: MenACWY-CRM Conjugate Vaccine + Combined Tetanus, Reduced Diphtheria Toxoid, Acellular Pertussis Vaccine + Quadrivalent Human Papillomavirus Vaccine

• Study Type: Interventional
• Enrollment (Actual): 801
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Genoa
    • Via Pastore, 1, Genoa, Italy, 16132
      • HOSPITAL"SAN MARTINO". Department of Health Sciences University of Genoa
  • Novara
    • Corso Mazzini, 18, Novara, Italy, 28100
      • Hospital "Maggiore della Carità". Pediatric Clinic
  • Taranto
    • Viale Magna Grecia, 173, Taranto, Italy, 74016
      • Hospital of Taranto- Unit of Hygiene and Publich Health Vaccination Center
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Birmingham Pediatrics, 806 Saint Vincent's Drive, Suite 615
  • California
    • Fremont, California, United States, 68025
      • Prairie Fields Family Medicine, 350 W. 23rd Street, Suite A
    • Madera, California, United States, 93637
      • Madera Family Medical Group, 1111 W. Fourth Street
  • Colorado
    • Colorado Springs, Colorado, United States, 80922
      • Clinical Research Advantage / Colorado Springs Health Partners, 6340 Barnes Road
  • Florida
    • Dayton, Florida, United States, 45406
      • Dayton Clinical Research, 1100 Salem Ave
    • Lake Mary, Florida, United States, 32746
      • Altamonte Pediatric Associates, 101 N. Country Club Rd. #113
  • Georgia
    • Marietta, Georgia, United States, 30062
      • Pediatrics and Adolescent Medicine, 2155 Post Oak Tritt Road, Suite 100
  • Iowa
    • Council Bluffs, Iowa, United States, 51503
      • Clinical Research Advantage / Ridge Family Physicians, 201 Ridge Street, Suite 201
  • Maryland
    • Columbia, Maryland, United States, 21045
      • Columbia Medical Practice, 5450 Knoll North Drive, Suite 215
  • Massachusetts
    • Boston, Massachusetts, United States, 02130
      • Roslindale Pediatrics Associates, 1153 Centre Street, Suite 31
  • Nebraska
    • Bellevue, Nebraska, United States, 68005
      • Bellevue Family Practice, 2206 Longo Suite 201
    • Lincoln, Nebraska, United States, 68505
      • Complete Children's Health, 8201 Northwoods Drive
    • Omaha, Nebraska, United States, 68134
      • Meridian Clinical Research, 3319 North, 107th Street
  • New York
    • Woodstock, New York, United States, 30189
      • Pediatrics and Adolescent Medicine, 120 Stonebridge Parkway, Suite 410
  • North Carolina
    • Raleigh, North Carolina, United States, 27609
      • Capitol Pediatrics and Adolescent Center, 3801 Computer Drive Suite 200
  • Ohio
    • Huber Heights, Ohio, United States, 45424
      • Ohio Pediatric Research Association, 7371 Brandt Pike Suite C
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • Omega Medical Research, 400 Bald Hill Road

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 14 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Individuals eligible for enrollment in this study were female and male individuals who had been shown to be healthy and who were:

1. 11-18 years of age inclusive who had given their written consent/assent and if applicable, whose parents or legal guardians had given written informed consent at the time of enrollment;

   • Available for all visits and telephone calls scheduled for the study;

   • In good health as determined by:

     • Medical history
     • Physical assessment
     • Clinical judgment of the investigator
2. Had been properly vaccinated against diphtheria, tetanus, and pertussis per local regulations;
3. Subjects who were current with childhood DTP-containing vaccinations per local guidelines. Any previous vaccinations containing DTP must have been received at least 5 years before study enrollment and no prior adolescent vaccinations (11-18 years of age) containing DTP vaccines were allowed.
4. For female subjects, who had a negative urine pregnancy test.
5. Any female subject who is sexually active committed to practice appropriate birth control.

Exclusion Criteria:

Individuals not eligible to be enrolled in the study were those:

1. Who were unwilling to give their written assent / consent
2. Who were breastfeeding
3. Who was, and/or whose parents or legal guardians were perceived to be unreliable or unavailable for the duration of the study period
4. Who had previous confirmed or suspected disease caused by N. meningitidis
5. Who had household contact with and/or intimate exposure to an individual with culture-proven N. meningitidis infection within 60 days prior to enrollment
6. Who had previously been immunized with a meningococcal vaccine or vaccine containing meningococcal antigen(s) (licensed or investigational). (Exception: Receipt of OMP-containing Hib vaccines was permitted)
7. Who had received prior human papillomavirus (HPV) vaccine
8. Who had received investigational agents or vaccines within 30 days prior to enrollment or who expected to receive an investigational agent or vaccine prior to completion of the study

9. Who had received live licensed vaccines within 30 days and inactive vaccine within 15 days prior to enrollment or for whom receipt of a licensed vaccine is anticipated during the study period.

   (Exception: Influenza vaccine could be administered up to 15 days prior to each study immunization and no less than 15 days after each study vaccination)

10. Who had experienced, within the 7 days prior to enrollment, significant acute or chronic infection (for example requiring systemic antibiotic treatment or antiviral therapy) or had experienced fever (defined as body temperature ≥ 38°C) within 3 days prior to enrollment

11. Who had any serious acute, chronic or progressive disease such as

    • History of cancer
    • Complicated diabetes mellitus
    • Advanced arteriosclerotic disease
    • Autoimmune disease
    • HIV infection or AIDS
    • Blood dyscrasias
    • Congestive heart failure
    • Renal failure
    • Severe malnutrition (Note: Subjects with mild asthma were eligible for enrollment. Subjects with moderate or severe asthma requiring routine use of inhaled or systemic corticosteroids were not eligible for enrollment)
12. Who had epilepsy, any progressive neurological disease or history of Guillain-Barre syndrome
13. Who had a history of anaphylaxis, serious vaccine reactions, or allergy to any vaccine component, including latex allergy

14. Who had a known or suspected impairment/alteration of immune function, either congenital or acquired or resulting from (for example):

    • Receipt of immunosuppressive therapy within 30 days prior to enrollment (systemic corticosteroids administered for more than 5 days, or in a daily dose > 1 mg/kg/day prednisone or equivalent during any of 30 days prior to enrollment, or cancer chemotherapy)
    • Receipt of immunostimulants
    • Receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within 90 days prior to enrollment and for the full length of the study
15. Who were known to have a bleeding diathesis, or any condition that may be associated with a prolonged bleeding time;
16. Who have Down's syndrome or other known cytogenic disorders;
17. Who and/or whose families were planning to leave the area of the study site before the end of the study period;
18. Who had any condition that, in the opinion of the investigator, might interfere with the evaluation of the study objectives.
19. Who were relatives of the study personnel.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo + Tdap + HPV; This group will receive Tdap, HPV and placebo concomitantly for the first vaccination. The second and third doses of HPV vaccine will be administered to all subjects 2 and 6 months after the first dose. All subjects will have serum samples collected at Visit 1 (baseline), Visit 2 (31 days) and Visit 5 (7 months after visit 1) for serology testing.	Biological: Placebo + Combined Tetanus, Reduced Diphtheria Toxoid, Acellular Pertussis Vaccine + Quadrivalent Human Papillomavirus Vaccine; All three vaccines were administered concomitantly. Quadrivalent Human Papillomavirus [Types 6, 11, 16, 18] Recombinant Vaccine is GARDASIL®. Reduced Diphtheria Toxoid, Acellular Pertussis Vaccine(Tdap) is Boostrix®.
Experimental: MenACWY-CRM + Tdap + HPV; This group will receive Tdap, HPV and MenACWY-CRM concomitantly. The second and third doses of HPV vaccine will be administered to this group 2 and 6 months after the first dose. All subjects will have serum samples collected at Visit 1 (baseline), Visit 2 (31 days) and Visit 5 (7 months after visit 1) for serology testing.	Biological: MenACWY-CRM Conjugate Vaccine + Combined Tetanus, Reduced Diphtheria Toxoid, Acellular Pertussis Vaccine + Quadrivalent Human Papillomavirus Vaccine; All three vaccines were administered concomitantly. MenACWY-CRM contains diphtheria-like toxoid as carrier for the capsular polysaccharides. Quadrivalent Human Papillomavirus [Types 6, 11, 16, 18] Recombinant Vaccine is GARDASIL®. Reduced Diphtheria Toxoid,Acellular Pertussis Vaccine(Tdap) is Boostrix®.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentages of Subjects With Anti-diphtheria and Anti-tetanus Antibody Concentrations ≥ 0.1 IU/mL When Tdap is Administered Concomitantly With HPV and MenACWY-CRM Vaccine Compared to Tdap Given Concomitantly With HPV and Placebo	The percentages of subjects with anti-diphtheria and anti-tetanus antibody concentrations ≥ 0.1 IU/mL (as measured by ELISA) following concomitant administration of Tdap with HPV and MenACWY-CRM vaccine as compared to concomitant administration of Tdap with HPV and placebo.	1 month post Tdap vaccination.
Geometric Mean Concentrations of Antibodies Against Pertussis Antigens After Concomitant Administration of Tdap With HPV and MenACWY-CRM Compared to Concomitant Administration of Tdap With HPV and Placebo	The geometric mean concentrations (GMCs) of antibodies against pertussis antigens (PT, FHA and PRN), as measured by ELISA, following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo.	1 month post Tdap vaccination.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean hSBA Titers Against N. Meningitidis Serogroups A,C,W and Y at 1 Month After Men ACWY Vaccination.	The immunogenicity was assessed in terms of geometric mean hSBA titers of MenACWY when administered concomitantly with Tdap and HPV at 1 month after 1 dose of MenACWY vaccination.	1 month post MenACWY-CRM vaccination.
Number of Subjects With Solicited Local and Systemic Adverse Events When Tdap and HPV Are Concomitantly Administered With MenACWY-CRM Compared to When Tdap and HPV Are Concomitantly Administered With Placebo	The number of subjects reporting solicited local and systemic reactions following concomitant administration of MenACWY-CRM vaccine, Tdap and HPV vaccine as compared to concomitant administration of placebo with Tdap and HPV.	Day 1-7 after any vaccination.
Number of Subjects With Unsolicited Adverse Events When Tdap and HPV Are Concomitantly Administered With MenACWY-CRM Compared to When Tdap and HPV Are Concomitantly Administered With Placebo	The number of subjects reporting any unsolicited adverse reactions (AEs) when Tdap and HPV are concomitantly administered with MenACWY-CRM as compared to when Tdap and HPV vaccine are concomitantly administered with placebo. Note: A total of 2 MenACWY-CRM+Tdap+HPV subjects reported AEs leading to premature withdrawal - one subject due to treatment emergent AE and another subject prior to study vaccination on day 1.	Throughout the study (Day 1 to Day 211).

Collaborators and Investigators

• Sponsor: Novartis
• Collaborators: Novartis Vaccines

Publications and helpful links

General Publications

• Miao Y, Mzolo T, Pellegrini M. Immunogenicity of a Quadrivalent Human Papillomavirus Vaccine When Co-Administered with Tetanus-Reduced Diphtheria-Acellular Pertussis and Quadrivalent Meningococcal Conjugate Vaccines in Healthy Adolescents: Results from a Randomized, Observer-Blind, Controlled Trial. Infect Dis Ther. 2019 Sep;8(3):335-341. doi: 10.1007/s40121-019-00258-5. Epub 2019 Aug 3.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: August 23, 2011
• First Submitted That Met QC Criteria: August 26, 2011
• First Posted (Estimate): August 29, 2011

Study Record Updates

• Last Update Posted (Estimate): February 14, 2014
• Last Update Submitted That Met QC Criteria: January 21, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: meningitis; pertussis; tetanus; human papillomavirus; diptheria
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Meningococcal Infections; Neisseriaceae Infections; Meningitis, Meningococcal; Meningitis; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: V59_40; 2011-000476-34 (EudraCT Number)