Clinical trial NCT02993757: Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Gardasil®
Official title: Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Gardasil® in Healthy Subjects Aged 9 to 13 Years in Malaysia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Dengue Fever
Dengue Hemorrhagic Fever
Human Papillomavirus Disease
Keywords: Dengue Fever
Dengue Hemorrhagic Fever
Human Papillomavirus Disease
CYD Dengue Vaccine
Dengvaxia®
Gardasil®
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2016-12-15
Enrollment: 528
Sex: ALL
Minimum age (years): 9
Maximum age (years): 13
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The aim of the study was to assess the safety and immunogenicity of the CYD dengue vaccine and Gardasil (Human Papillomavirus Quadrivalent \[Types 6, 11, 16, and 18\] Vaccine, Recombinant) when administered concomitantly or sequentially.

Primary objectives:

* To demonstrate that the humoral immune response (in terms of geometric mean titers \[GMTs\]) to Gardasil after concomitant administration was non-inferior to sequential administration with the CYD dengue vaccine measured 28 days after the last dose of Gardasil.
* To demonstrate that the humoral immune response to the CYD dengue vaccine after concomitant administration was non-inferior to sequential administration with Gardasil measured 28 days after the last dose of the CYD dengue vaccine.

Secondary Objectives:

* To demonstrate that the humoral immune response (in terms of seroconversion) to Gardasil vaccine after concomitant administration was non-inferior to sequential administration with the CYD dengue vaccine measured 28 days after the last dose of Gardasil.
* To describe the humoral immune response to Gardasil at baseline and after each dose of Gardasil in each and any group.
* To describe the humoral immune response to the CYD dengue vaccine at baseline and after each dose of the CYD dengue vaccine in each and any group.
* To describe the safety of Gardasil and the CYD dengue vaccine after each and any dose in each group.

Detailed description: Participants received 3 doses of CYD dengue vaccine and 2 doses of Gardasil administered either concomitantly or sequentially.

The study activities were put on hold for several months (up to 6 months for some participants) to obtain the approval of Protocol Amendment 1 by the competent authorities and completed the associated logistic tasks. Due to this protocol amendment as per Independent Data Monitoring Committee recommendation, only previously dengue immune participants (seropositive for dengue before vaccination) were eligible to complete the vaccination schedule. Dengue non-immune participants (seronegative for dengue before vaccination) did not receive any additional CYD dengue vaccine injections, but were followed for safety up to 6 months after the last injection.

Due to the change in amendment 1, the number of evaluable dengue immune participants at baseline did not meet the predefined number of participants that would have allowed for a global power of at least 80% for non-inferiority testing of Gardasil vaccine and CYD dengue vaccine (121 per group for the co-primary objectives and 194 per group for the secondary objectives).

All participants were assessed for immunogenicity and safety. Safety assessments included solicited reactions within 7 or 14 days after each injection, unsolicited adverse events (AEs) within 28 days after each injection, non-serious AEs of Special Interests (AESIs) within 7 days after each injection, and serious adverse events including AESI and hospitalized virologically-confirmed dengue cases during the study period.

Eligibility criteria: Inclusion Criteria:

* Participants aged 9 to 13 years (i.e., from the day of the 9th birthday to the day prior to the 14th birthday) on the day of inclusion.
* Informed consent form (ICF) or Assent form (AF) had been signed and dated by the participant (based on local regulations), and/or ICF had been signed and dated by the parent(s) or another legally acceptable representative (and by an independent witness if required by local regulations).
* Participant (or participant and parent\[s\] or another legally acceptable representative) was (were) able to attend all scheduled visits and complied with all trial procedures.
* Participant in good health, based on medical history, and physical examination.

Exclusion Criteria:

* Participant was pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female had to be pre-menarche, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination and until at least 4 weeks after the last vaccination).
* Participation at the time of study enrollment (or in the 4 weeks preceding the first trial vaccination) or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure.
* Planned receipt of any vaccine in the 4 weeks following any trial vaccination.
* Previous vaccination against dengue disease with the trial vaccine.
* Previous vaccination against human papillomavirus (HPV) disease with either the trial vaccine or another vaccine.
* Receipt of immune globulins, blood or blood-derived products in the past 3 months.
* Known or suspected congenital or acquired immunodeficiency (including human immunodeficiency virus infection with impaired immune function); 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).
* History of HPV infection, confirmed either clinically, serologically, or microbiologically as reported by participant or parent(s) or another 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.
* Thrombocytopenia, contraindicating IM vaccination.
* Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating IM vaccination.
* Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
* Current alcohol abuse or drug addiction that, based on investigator's judgment, might interfered with the participant's ability to comply with trial procedures.
* Chronic illness that, in the opinion of the Investigator, was at a stage where it might interfered with trial conduct or completion.
* Identified as an Investigator or employee of the Investigator with direct involvement in the proposed study, or identified as an immediate family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study.
* Self-reported Hepatitis B, Hepatitis C infection.

Primary outcomes:
measure: Geometric Mean Titers (GMTs) Against Each Gardasil Vaccine Human Papillomavirus (HPV) Antigen (HPV-6, HPV-11, HPV-16, HPV-18) 28 Days After Last Gardasil Vaccination in the Previously Dengue Immune Participants
timeFrame: 28 days after the last Gardasil vaccination
measure: Geometric Mean Titers Against Each Parental Dengue Virus Serotype 28 Days After Third CYD Dengue Vaccination in the Previously Dengue Immune Participants
timeFrame: 28 days after third CYD dengue vaccination
Secondary outcomes:
measure: Percentage of Participants With Seroconversion Against Each Gardasil HPV Antigen (HPV-6, HPV-11, HPV-16, HPV-18) 28 Days After Last Dose of Gardasil in the Previously Dengue Immune Participants
timeFrame: 28 days after the last Gardasil vaccination
measure: Geometric Mean Titers Against Each Gardasil HPV Antigen (HPV-6, HPV-11, HPV-16, HPV-18) at Day 0 and 28 Days After Each Dose of Gardasil in the Previously Dengue Immune Participants
timeFrame: Day 0 (pre-vaccination) and 28 days after Gardasil vaccination 1 and 2
measure: Geometric Mean Titers Against Each Dengue Virus Serotype of CYD Dengue Vaccine at Day 0 and 28 Days After Each Dose of CYD Dengue Vaccination in the Previously Dengue Immune Participants
timeFrame: Day 0 (pre-vaccination) and 28 days after each CYD dengue vaccination
measure: Percentage of Participants With Neutralizing Antibody Titers Against Each of the 4 Dengue Virus Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in the Previously Dengue Immune Participants
timeFrame: Day 0 (pre-vaccination) and 28 days after each CYD dengue vaccination
measure: Percentage of Participants With Neutralizing Antibody Titers Above Pre-defined Thresholds Against at Least 1,2,3,or4 Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in Previously Dengue Immune Participants
timeFrame: Day 0 (pre-vaccination) and 28 days after each CYD dengue vaccination
measure: Number of Participants Reporting Immediate Adverse Events (AEs) Following Vaccination With Gardasil or CYD Dengue Vaccine
timeFrame: Within 30 minutes after any and each vaccination
measure: Number of Participants Reporting Solicited Injection Site Reactions Following Vaccination With Gardasil or CYD Dengue Vaccine
timeFrame: Up to 7 days after any and each vaccination
measure: Number of Participants Reporting Solicited Systemic Reactions Following Vaccination With Gardasil or CYD Dengue Vaccine
timeFrame: Up to 14 days after any and each vaccination
measure: Number of Participants Reporting Unsolicited Adverse Events Following Vaccination With Gardasil or CYD Dengue Vaccine
timeFrame: Up to 28 days after any and each vaccination
measure: Number of Participants Reporting Non-serious Adverse Event of Special Interests (AESIs) Following Vaccination With Gardasil or CYD Dengue Vaccine
timeFrame: Within 7 days after any and each vaccination
measure: Number of Participants Reporting Serious Adverse Events (SAEs) Including Serious Adverse Event of Special Interests Following Vaccination With Gardasil or CYD Dengue Vaccine
timeFrame: From Day 0 up to 6 months after the last Gardasil or CYD vaccination
measure: Number of Participants Reporting Cases of Virologically Confirmed Dengue (VCD) Hospitalization Following Vaccination With Gardasil or CYD Dengue Vaccine
timeFrame: From Day 0 up to 6 months after the last Gardasil or CYD vaccination
Other outcomes:
Locations:
city: Klang
country: Malaysia
facility: Sanofi Pasteur Investigational Site 004
city: Kuala Lumpur
country: Malaysia
facility: Sanofi Pasteur Investigational Site 005
city: Kuala Lumpur
country: Malaysia
facility: Sanofi Pasteur Investigational Site 001
city: Kuantan
country: Malaysia
facility: Sanofi Pasteur Investigational Site 003
city: Sibu
country: Malaysia
facility: Sanofi Pasteur Investigational Site 002
Study officials:
affiliation: Sanofi Pasteur SA
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Hassan J, Toh TH, Sivapunniam SK, Hasim R, Ghazali NF, Sulaiman S, Koh MT, Meyer S, Toh ML, Zocchetti C, Vigne C, Mascarenas C. Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Quadrivalent Human Papillomavirus Vaccine in Boys and Girls 9-13 Years of Age in Malaysia: A Phase IIIb, Randomized, Open-label Study. Pediatr Infect Dis J. 2021 Aug 1;40(8):774-781. doi: 10.1097/INF.0000000000003164.