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

Phase 3

Completed

• Conditions: Dengue Fever
• Interventions: Biological: 9vHPV Vaccine; Biological: Dengue Tetravalent Vaccine (TDV)

• Registration Number: NCT04313244
• Lead Sponsor: Takeda

Brief Summary

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.

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 Timeline

• Study First Submitted: 2020-03-16
• Study First Submitted QC: 2020-03-16
• Study First Posted: 2020-03-18
• Study Start: 2021-05-15
• Primary Completion: 2022-02-21
• Study Completion: 2022-07-19
• Disposition First Submitted: 2023-01-18
• Disposition First Submitted QC: 2023-01-18
• Disposition First Posted: 2023-01-20
• Status Verified: 2024-01
• Results First Submitted: 2024-01-16
• Results First Submitted QC: 2024-01-16
• Last Update Submitted: 2024-01-16
• Results First Posted: 2024-02-07
• Last Update Posted: 2024-02-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 614

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
9vHPV+TDV	9vHPV Vaccine	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).
9vHPV+TDV	Dengue Tetravalent Vaccine (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).
9vHPV	9vHPV Vaccine	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).

Primary Outcome Measures

Name	Time	Method
Geometric Mean Titers (GMTs) for Human Papillomavirus (HPV) Types 6, 11, 16, 18, 31, 33, 45, 52, 58	Day 210 (Month 7)	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.

Secondary Outcome Measures

Name	Time	Method
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)	Day 210 (Month 7)	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.
Percentage of Participants With Solicited Local Adverse Events for 7 Days Following Vaccination by Severity	Up to 7 days (Day of vaccination + 6 subsequent days) after each vaccination	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.
Percentage of Participants With Seropositivity for Multiple (2, 3 or 4) Dengue Serotypes	Day 120 (Month 4)	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.
GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes	Day 120 (Month 4)	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.
Percentage of Participants With Any Unsolicited AEs for 28 Days Following Vaccination	Up to 28 days (Day of vaccination + 27 subsequent days) after each 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.
Percentage of Participants With Seropositivity for Each of the 4 Dengue Serotypes	Day 120 (Month 4)	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.
Percentage of Participants With Solicited Systemic Adverse Events (AEs) for 14 Days Following Vaccination by Severity	Up to 14 days (Day of vaccination + 13 subsequent days) after each vaccination	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.
Percentage of Participants With Serious Adverse Events (SAEs)	From first vaccination (Day 1 [Month 0]) through end of study (Day 360 [Month 12])	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.

Trial Locations

Locations (4)

Siriraj Hospital; 🇹🇭 Bangkoknoi, Khet Bangkok Noi, Thailand

King Chulalongkorn Memorial Hospital; 🇹🇭 Bangkok, Thailand

The Hospital for Tropical Diseases; 🇹🇭 Bangkok, Thailand

Thammasat University Hospital; 🇹🇭 Pathum Thani, Thailand