Study of a Booster Injection of Pentaxim™ Vaccine Administered With Dengue Vaccine in Healthy Toddlers

• ClinicalTrials.gov Identifier: NCT01411241
• Recruitment Status: Completed
• First Posted: August 8, 2011
• Results First Posted: July 29, 2019
• Last Update Posted: July 29, 2019
• Sponsor: Sanofi Pasteur, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Sanofi Pasteur, a Sanofi Company )

Study Description

Brief Summary:

The aim of the study was to assess whether the second CYD dengue vaccination could be administered concomitantly with the booster vaccination of a pediatric combination vaccine (Pentaxim™) during the same day visit but in 2 different sites of administration.

Primary Objective:

• To demonstrate the non-inferiority of the antibody response against all antigens (diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b (Hib)) in participants receiving one booster dose of Pentaxim™ vaccine administered concomitantly with the second dose of CYD dengue vaccine compared to participants receiving one booster dose of Pentaxim™ vaccine administered concomitantly with placebo.

Secondary Objectives:

• To describe the safety of Pentaxim™ vaccine administered concomitantly with the second dose of CYD dengue vaccine, or administered concomitantly with placebo.
• To describe the safety of the CYD dengue vaccine after the second dose of CYD dengue vaccine administered concomitantly with Pentaxim™ vaccine (at Visit 05) or administered alone (at Visit 06).
• To describe the safety of the CYD dengue vaccine in all participants after each dose.
• To describe the antibody response to each dengue virus serotype (post-Dose 2 and post-Dose 3) after the second dose of CYD dengue vaccine administered concomitantly with Pentaxim vaccine (at Visit 05) or administered alone (at Visit 06).
• To describe the antibody response to each dengue virus serotype post-Dose 2 and post-Dose 3.

Condition or disease	Intervention/treatment	Phase
Dengue; Dengue Hemorrhagic Fever	Biological: Live, attenuated, recombinant dengue serotype 1, 2, 3, and 4 virus; Biological: DTaP IPV//Hib vaccine; Biological: Placebo; Biological: Measles, mumps, and rubella vaccine; Biological: Pneumococcal vaccine	Phase 3

Detailed Description:

Participants required 8 or 9 clinic visits and received a total of 7 injections. The dengue post-vaccinal viremia was assessed at Visit 2 from a subset of toddlers. The dengue immunogenicity was assessed 28 days after CYD dengue dose 2 and dose 3 from a subset of toddlers. Participants were followed-up for safety after each vaccine dose and for 6 months after the last dengue vaccination.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 720 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: An observer-blind design was chosen since the products were visually different. For the second dose of CYD dengue vaccine, the person who administered the injections knew which product was administered while the subject/parent and Investigator were blinded. The first and third doses of CYD dengue vaccine were administered according to an open-label procedure. A placebo dose was administered at Month 7(Group 1) and concomitantly with Pentaxim vaccine at Month 6 (Group 2) to maintain the blind.
• Primary Purpose: Prevention
• Official Title: Immunogenicity and Safety of a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly With Tetravalent Dengue Vaccine in Healthy Toddlers Aged 15 to 18 Months in Mexico
• Actual Study Start Date: July 18, 2011
• Actual Primary Completion Date: February 4, 2014
• Actual Study Completion Date: April 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: CYD Dengue Vaccine Group 1; Participants received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a measles, mumps, rubella (MMR) vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), a booster dose of Pentaxim vaccine was administered concomitantly with the second injection of CYD dengue vaccine at Month 6 (15 to 18 months of age), placebo at Month 7 (16 to 19 months of age) to maintain the blind, and the third injection of CYD dengue vaccine at Month 12 (21 to 24 months).	Biological: Live, attenuated, recombinant dengue serotype 1, 2, 3, and 4 virus; 0.5 mL, subcutaneous at age 9 to 12, 15 to 18 and 21 to 24 months.; Other Name: CYD Dengue Vaccine; Biological: DTaP IPV//Hib vaccine; 0.5 mL, intramuscular; Other Name: Pentaxim™; Biological: Placebo; 0.5 mL, subcutaneous; Other Name: NaCl; Biological: Measles, mumps, and rubella vaccine; 0.5 mL, subcutaneous; Other Name: Trimovax®; Biological: Pneumococcal vaccine; 0.5 mL, intramuscular; Other Name: Prevenar®
Experimental: CYD Dengue Vaccine Group 2; Participants received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a MMR vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), the Pentaxim vaccine was administered concomitantly with placebo at Month 6 (15 to 18 months of age) to maintain the blind, a second injection of CYD dengue vaccine at Month 7 (16 to 19 months of age), and the third injection of CYD dengue vaccine at Month 12 (21 to 24 months).	Biological: Live, attenuated, recombinant dengue serotype 1, 2, 3, and 4 virus; 0.5 mL, subcutaneous at age 9 to 12, 16 to 19 and 21 to 24 months; Other Name: CYD Dengue Vaccine; Biological: DTaP IPV//Hib vaccine; 0.5 mL, intramuscular; Other Name: Pentaxim™; Biological: Placebo; 0.5 mL, subcutaneously; Other Name: NaCl; Biological: Measles, mumps, and rubella vaccine; 0.5 mL, subcutaneous; Other Name: Trimovax®; Biological: Pneumococcal vaccine; 0.5 mL, intramuscular; Other Name: Prevenar®

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Seroprotection or Booster Response After a Booster Injection (Inj.) of Diphtheria, Tetanus, Acellular Pertussis(DTaP)-Inactivated Polio Virus (IPV)//Hib (Pentaxim™) Administered Concomitantly With CYD Dengue Vaccine [ Time Frame: 28 days post-injection ]
   Antibodies (Ab) against diphtheria, tetanus toxoid, pertussis toxoid (PT), and filamentous hemaglutinin (FHA) was measured by enzyme-linked immunosorbent assay (ELISA), polyribosylribitol phosphate (PRP) by Farr-type radioimmunoassay, and poliovirus types 1, 2, and 3 by seroneutralization assay. Seroprotection was defined as >=0.1 International Unit (IU)/mL for diphtheria toxoid and tetanus toxoid, >=8 1/dil for poliovirus types 1, 2, and 3, and >=1.0 μg/mL for PRP. Booster response to PT and FHA: participants whose pre-vaccination Ab titers were < lower limit of quantitation (LLOQ), a booster response occurred if they had post-vaccination levels >=4* LLOQ; participants whose pre-vaccination Ab concentrations were >=LLOQ but <4* LLOQ, a booster response occurred if they had a 4-fold increase (post/pre-vaccination levels >=4); for participants whose pre-vaccination Ab concentrations were >=4* LLOQ, a booster response occurred if they had a 2-fold increase (post/pre-vaccination >=2).

Secondary Outcome Measures :

1. Geometric Mean Titers Against Each Serotype With the Parental Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly With CYD Dengue Vaccine [ Time Frame: Pre-injection 1 and 28 days post-injection 2 and 3 ]
   Geometric mean titers of antibodies against the dengue virus serotypes were measured by dengue plaque reduction neutralization test (PRNT).
2. Geometric Mean Titer Ratios Against Each Serotype With the Parental of Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly With CYD Dengue Vaccine [ Time Frame: Pre-injection 1 and 28 days post-injection 2 and 3 ]
   Geometric mean titers of antibodies against the dengue virus serotypes were measured by dengue PRNT.
3. Percentage of Participants With a Seropositivity Against Each Serotype With the Parental Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly With CYD Dengue Vaccine [ Time Frame: Pre-injection 1 and 28 days post-injection 2 and 3 ]
   Seropositivity against each dengue virus serotype (parental strains) were measured by dengue PRNT. Seropositivity was defined as antibody titers >=10 (1/dilution).
4. Percentage of Participants With Seropositivity Against at Least One, Two, Three, or Four Serotypes With the Parental Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV// Hib (Pentaxim™) Administered With CYD Dengue Vaccine [ Time Frame: Pre-injection 1 and 28 days post-injection 2 and 3 ]
   Seropositivity against each dengue virus serotype (parental strains) were measured by dengue PRNT. Seropositivity was defined as antibody titers >=10 (1/dilution).
5. Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following the First Injection With CYD Dengue Vaccine [ Time Frame: Day 0 up to Day 14 post-first injection ]
   Solicited injection site reactions: Tenderness, Erythema, and Swelling. Solicited systemic reactions: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability. Grade (Grd) 3 Solicited injection site reactions: Tenderness, cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling: >=50 mm. Grade 3 Solicited systemic reactions: Fever: >39.5 degree Celsius (°C); Vomiting: >=6 episodes per 24 hours or requiring parenteral hydration; Crying abnormal: >3 hours; Drowsiness: Sleeping most of the time or difficult to wake up; Appetite lost: refuses >=3 feeds/meals or refuses most feeds/meals; Irritability: inconsolable.
6. Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following a Booster Injection of DTaP-IPV// Hib (Pentaxim™) Administered Concomitantly With Either CYD Dengue Vaccine or a Placebo Vaccine [ Time Frame: Day 0 up to Day 14 post-booster injection ]
   Solicited injection site reactions: Tenderness, Erythema, and Swelling. Solicited systemic reactions: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability. Grade 3 Solicited injection site reactions: Tenderness: cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling: >=50 mm. Grade 3 Solicited systemic reactions: Fever: >39.5°C; Vomiting: >=6 episodes per 24 hours or requiring parenteral hydration; Crying abnormal: >3 hours; Drowsiness: sleeping most of the time or difficult to wake up; Appetite lost: refuses >=3 feeds/meals or refuses most feeds/meals; Irritability: inconsolable; and Extensive swelling, severe.
7. Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following a Second Injection of CYD Dengue Vaccine or a Placebo Vaccine [ Time Frame: Day 0 up to Day 14 post-second injection ]
   Solicited injection site reactions: Tenderness, Erythema, and Swelling. Solicited systemic reactions: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability. Grade 3 Solicited injection site reactions: Tenderness: cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling: >=50 mm. Grade 3 Solicited systemic reactions: Fever: >39.5°C; Vomiting: >=6 episodes per 24 hours or requiring parenteral hydration; Crying abnormal: >3 hours; Drowsiness, Sleeping most of the time or difficult to wake up; Appetite lost: refuses >=3 feeds/meals or refuses most feeds/meals; Irritability: inconsolable.
8. Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following a Third Injection of CYD Dengue Vaccine [ Time Frame: Day 0 up to Day 14 post-third injection ]
   Solicited injection site reactions: Tenderness, Erythema, and Swelling. Solicited systemic reactions: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability. Grade 3 Solicited injection site reactions: Tenderness: cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling: >=50 mm. Grade 3 Solicited systemic reactions: Fever: >39.5°C; Vomiting: >=6 episodes per 24 hours or requiring parenteral hydration; Crying abnormal: >3 hours; Drowsiness: sleeping most of the time or difficult to wake up; Appetite lost: refuses >=3 feeds/meals or refuses most feeds/meals; Irritability: inconsolable.

Eligibility Criteria

• Ages Eligible for Study: 9 Months to 12 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Aged 9 to 12 months on the day of inclusion.
• Born at full term of pregnancy (>= 37 weeks) and with a birth weight >= 2.5 kg.
• Participant in good health, based on medical history and physical examination.
• Documentation of completion of the primary vaccination series with Pentaxim vaccine with the 3 doses received between 2 and 8 months of age.
• Informed consent form had been signed and dated by both parents or other legally acceptable representative (and by 2 mandatory witnesses as required by local regulations).
• Participant and parent/guardian attended all scheduled visits and comply with all trial procedures.

Exclusion Criteria:

• Participation in another clinical trial investigating a vaccine, drug, medical device, or medical procedure in the 4 weeks preceding the first trial vaccination.
• Planned participation in another clinical trial during the present trial period.
• Planned receipt of any vaccine in the 4 weeks following any trial vaccination.
• Previous vaccination against flavivirus diseases, measles, mumps, rubella, previous booster vaccination against pneumococcal diseases, diphtheria, tetanus, pertussis, Hib and/or polio.
• Receipt of blood or blood-derived products in the past 3 months which might interfere with assessment of the immune response.
• Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months).
• Personal seropositivity for human immunodeficiency virus (HIV) or hepatitis C as reported by the parent(s)/legally acceptable representative.
• History of pertussis and/or Hib infection as reported by the parent(s)/legally acceptable representative.
• Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccines used in the trial or to a vaccine containing any of the same substances.
• History of contraindication to the receipt of vaccines containing components of Pentaxim vaccine (diphtheria toxoid, tetanus toxoid, pertussis toxoid, filamentous hemagglutinin, polyribosylribitol phosphate [PRP] and polio) or of measles, mumps and rubella vaccine and of pneumococcal vaccine.
• Thrombocytopenia, as reported by the parent(s)/legally acceptable representative.
• Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination.
• History of central nervous system disorder or disease, including seizures.
• Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere with trial conduct or completion.
• Identified as a child (adopted or natural) of the Investigator or of site employees of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center.

Contacts and Locations

Locations

Mexico

Acapulco, Guerrero, Mexico, CP 39670

Guadalajara, Jalisco, Mexico, CP 44280

Monterrey, Nuevo Leon, Mexico, CP 64460

Merida, Yucatan, Mexico, CP 97000

Sponsors and Collaborators

Sanofi Pasteur, a Sanofi Company

Investigators

• Study Director: Medical Director; Sanofi Pasteur SA

More Information

Additional Information:

Related Info  Related Info 

• Responsible Party: Sanofi Pasteur, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT01411241 History of Changes
• Other Study ID Numbers: CYD33; U1111-1115-6290 ( Other Identifier: WHO )
• First Posted: August 8, 2011
• Results First Posted: July 29, 2019
• Last Update Posted: July 29, 2019
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/

Keywords provided by Sanofi ( Sanofi Pasteur, a Sanofi Company ):

Dengue; Dengue Hemorrhagic Fever; CYD Dengue Vaccines; Pentaxim™

Additional relevant MeSH terms:

Dengue; Hemorrhagic Fevers, Viral; Severe Dengue; Arbovirus Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Vaccines; Heptavalent Pneumococcal Conjugate Vaccine; Immunologic Factors; Physiological Effects of Drugs