Immunogenicity and Safety of Dengue Tetravalent Vaccine (TDV) and Recombinant 9-valent Human Papillomavirus Vaccine (9vHPV) in Participants Aged ≥9 to <15 Years

A Phase 3, Open-Label, Randomized Trial to Investigate the Immunogenicity and Safety of the Co-administration of a Subcutaneous Dengue Tetravalent Vaccine (Live, Attenuated) (TDV) and an Intramuscular Recombinant 9-Valent Human Papillomavirus (9vHPV) Vaccine in Subjects Aged ≥9 to <15 Years in an Endemic Country for Dengue

The purpose of the study is to demonstrate the non-inferiority (NI) of the immune response to 2 doses of 9vHPV vaccine, 1 co-administered with TDV, compared with 2 doses of 9vHPV vaccine administered alone.

Study Overview

• Status: Completed
• Conditions: Dengue Fever
• Intervention / Treatment: Biological: Dengue Tetravalent Vaccine (TDV); Biological: 9vHPV Vaccine

Detailed Description

The vaccine being tested in this study is called Tetravalent Dengue Vaccine (TDV). The study will assess the immunogenicity and safety on the co-administration of 9vHPV vaccine with TDV in healthy participants aged ≥9 to <15 years.

The study will enroll approximately 614 healthy volunteers. Participants will be randomly assigned to one of the two treatment groups-

• Group 1
• Group 2

All participants will receive recombinant 9-valent Human Papillomavirus Vaccine (9vHPV) intramuscular (IM) in combination with Dengue Tetravalent Vaccine (TDV) subcutaneous (SC) injection on Day 1 (Month 0 ) followed by 9vHPV on Day 90 (Month 3) and TDV on Day 180 (Month 6) in Group 1. Participants will receive 9vHPV on Day 1 (Month 0) and Day 180 (Month 6) IM in Group 2.

This multi-center trial will be conducted in Thailand. The overall time to participate in this study is 12 months. Participants will make multiple visits to the clinic, after last dose of study drug for a follow-up assessment.

• Study Type: Interventional
• Enrollment (Actual): 614
• Phase: Phase 3

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand, 10330
    • King Chulalongkorn Memorial Hospital
  • Bangkok, Thailand, 10400
    • The Hospital for Tropical Diseases
  • Pathum Thani, Thailand, 12121
    • Thammasat University Hospital
  • Khet Bangkok Noi
    • Bangkoknoi, Khet Bangkok Noi, Thailand, 10700
      • Siriraj Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 9 years to 14 years (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Participants who are in good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs), and the clinical judgment of the investigator.
2. Participants who can comply with trial procedures and are available for the duration of follow-up.

Exclusion Criteria:

1. Has an elevated oral temperature ≥38°C (≥100.4°F) within 3 days of the intended date of vaccination.
2. Participants with contraindications, warnings and/or precautions to vaccination with Recombinant 9-valent Human Papillomavirus Vaccine (9vHPV) vaccine as specified within the prescribing information.
3. Has any history of progressive or severe neurologic disorder, seizure disorder or neuro-inflammatory disease.

4. Known or suspected impairment/alteration of immune function, including:

   1. Chronic use of oral steroids (equivalent to 20 mg/day prednisone ≥12 weeks/≥2 mg/kg body weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (Month 0) (use of inhaled, intranasal, or topical corticosteroids is allowed).
   2. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone ≥12 weeks/≥2 mg/kg body weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (Month 0).
   3. Administration of immunoglobulins and/or any blood products within the 3 months prior to Day 1 (Month 0) or planned administration during the trial.
   4. Receipt of immunostimulants within 60 days prior to Day 1 (Month 0).
   5. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months prior to Day 1 (Month 0).
   6. Human immunodeficiency virus (HIV) infection or HIV-related disease.
   7. Hepatitis B virus infection.
   8. Hepatitis C virus infection.
   9. Genetic immunodeficiency.
5. Abnormalities of splenic or thymic function.
6. Has a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time.
7. Who received any other vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to enrollment in this trial or who are planning to receive any vaccine within 28 days of trial vaccine administration.
8. Who have used antipyretics and/or analgesic medications within 24 hours prior to vaccination. The reason for their use (prophylaxis versus treatment) must be documented. Trial entry should be delayed to allow for a full 24 hours to have passed since last use of antipyretics and/or analgesic medications.
9. Previous and planned vaccination (during the trial conduct), against any flavivirus (except Japanese encephalitis [JE]) including dengue, yellow fever (YF) viruses or tick-borne encephalitis.
10. Previous and planned vaccination (during the trial conduct) against HPV.
11. Previous participation in any clinical trial of a dengue or other flavivirus (eg, West Nile [WN] virus) candidate vaccine, except for participants who received placebo in those trials.
12. Has a current or previous infection with a flavivirus such as Zika, YF, JE, WN fever, tick-borne encephalitis or Murray Valley encephalitis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 9vHPV+TDV; Participants will receive 0.5 mL 9vHPV intramuscularly (IM) with 0.5 mL TDV subcutaneously (SC) once on Day 1 (Month 0) followed by 0.5 mL TDV SC once on Day 90 (Month 3) and 0.5 mL 9vHPV IM once on Day 180 (Month 6).	Biological: Dengue Tetravalent Vaccine (TDV); TDV subcutaneous injection; Other Names: TAK-003; Biological: 9vHPV Vaccine; 9vHPV intramuscular injection
Experimental: 9vHPV; Participants will receive 0.5 mL 9vHPV vaccine IM once on Day 1 (Month 0) followed by 0.5 mL 9vHPV vaccine IM once on Day 180 (Month 6).	Biological: 9vHPV Vaccine; 9vHPV intramuscular injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean Titers (GMTs) for Human Papillomavirus (HPV) Types 6, 11, 16, 18, 31, 33, 45, 52, 58	GMTs for HPV were measured by immunoglobulin G binding assay (IgGBA) assay. HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52 and HPV-58 were the types of HPV analyzed.	Day 210 (Month 7)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Seropositivity for HPV Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 as Measured by Immunoglobulin G Binding Assay (IgGBA)	Seropositive for HPV is defined as anti-HPV titers greater or equal to the prespecified cutoffs for any of the 9 HPV serotypes: HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52 and HPV-58, measured by IgGBA. The serostatus cut-off is the antibody titer level above the assay's lower limit of quantification that reliably distinguishes sera samples classified by clinical likelihood of HPV infection and positive or negative status by previous versions of IgGBA or equivalent assay. The serostatus cut-offs for the 9 HPV serotypes: HPV-6= 9, HPV-11= 6, HPV-16= 5, HPV-18= 5, HPV-31= 3, HPV-33= 4, HPV-45= 3, HPV-52= 5 and HPV-58= 5. Percentages are rounded off to the nearest decimal point.	Day 210 (Month 7)
GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes	GMTs of neutralizing antibodies for each of the 4 dengue serotypes were measured by microneutralization test 50% (MNT50). The four dengue serotypes: DENV-1, DENV-2, DENV-3 and DENV-4. As prespecified in the protocol, the data for this outcome measure was collected and analyzed for participants in the 9vHPV+TDV arm group only.	Day 120 (Month 4)
Percentage of Participants With Seropositivity for Each of the 4 Dengue Serotypes	Seropositivity is defined as a reciprocal neutralizing antibody titer ≥10 for any of the 4 dengue serotypes. The four dengue serotypes: DENV-1, DENV-2, DENV-3 and DENV-4. As prespecified in the protocol, the data for this outcome measure was collected and analyzed for participants in the 9vHPV+TDV arm group only. Percentages are rounded off to the nearest decimal point.	Day 120 (Month 4)
Percentage of Participants With Seropositivity for Multiple (2, 3 or 4) Dengue Serotypes	Seropositivity is defined as a reciprocal neutralizing antibody titer ≥10 for any of the 4 dengue serotypes. The dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositive for multiple dengue serotypes were summarized for categories with at least one participant with event: trivalent (seropositive for 3 dengue serotypes), and tetravalent (seropositive for all 4 dengue serotypes). As prespecified in the protocol, the data for this outcome measure was collected and analyzed for participants in the 9vHPV+TDV arm group only. Percentages are rounded off to the nearest decimal point.	Day 120 (Month 4)
Percentage of Participants With Solicited Local Adverse Events for 7 Days Following Vaccination by Severity	Solicited local adverse events (AEs) (at injection site) were collected by participants using diary cards within 7 days after vaccination and included: Pain [Grade 0 (no pain), 1 (mild: no interference with daily activity), 2 (moderate: interference with daily activity with or without treatment) and 3 (severe: prevents daily activity with or without treatment)]; erythema and swelling [Grade 0 (<25 millimeters [mm]), 1 (25 - ≤ 50 mm), 2 (>50 - ≤ 100 mm), 3 (> 100 mm)]. Percentages are rounded off to the nearest decimal point. The data for solicited local adverse events after any vaccination are presented. Only those categories with at least 1 participant with event are reported.	Up to 7 days (Day of vaccination + 6 subsequent days) after each vaccination
Percentage of Participants With Solicited Systemic Adverse Events (AEs) for 14 Days Following Vaccination by Severity	Solicited systemic AEs were collected by participants using diary cards within 14 days after vaccination and included fever, headache, asthenia, malaise, and myalgia. Severity grades were: Grade 0: none, Grade 1: mild (no interference with daily activity), Grade 2: moderate (interference with daily activity with or without treatment), Grade 3: severe (prevents normal daily activity with or without treatment). Fever is defined as body temperature greater than or equal to 38°C (100.4 degrees Fahrenheit [°F]). Only categories with at least one participant with event following any vaccination are reported. Percentages are rounded off to the nearest decimal point. The data for solicited systemic adverse events after any vaccination are presented.	Up to 14 days (Day of vaccination + 13 subsequent days) after each vaccination
Percentage of Participants With Any Unsolicited AEs for 28 Days Following Vaccination	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a study vaccine; it does not necessarily have to have a causal relationship with study vaccine administration. Percentages are rounded off to the nearest decimal point. The data for unsolicited adverse events after any vaccination are presented.	Up to 28 days (Day of vaccination + 27 subsequent days) after each vaccination
Percentage of Participants With Serious Adverse Events (SAEs)	An SAE is defined as any untoward medical occurrence or effect that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important which may require intervention to prevent the items listed above or may expose the participant to danger.	From first vaccination (Day 1 [Month 0]) through end of study (Day 360 [Month 12])

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Medical Director, Takeda

Publications and helpful links

Helpful Links

• To obtain more information about this study, click this link.

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2021
• Primary Completion (Actual): February 21, 2022
• Study Completion (Actual): July 19, 2022

Study Registration Dates

• First Submitted: March 16, 2020
• First Submitted That Met QC Criteria: March 16, 2020
• First Posted (Actual): March 18, 2020

Study Record Updates

• Last Update Posted (Actual): February 7, 2024
• Last Update Submitted That Met QC Criteria: January 16, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Drug therapy
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Arbovirus Infections; Vector Borne Diseases; Flavivirus Infections; Flaviviridae Infections; Hemorrhagic Fevers, Viral; Dengue; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: DEN-308; 2022-003339-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes