Safety and Immunogenicity With Two Different Serotype 2 Potencies of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) in Adults in Singapore

Phase 2

Completed

• Conditions: Dengue Fever
• Interventions: Biological: Takeda's Tetravalent Dengue Vaccine Candidate (TDV); Biological: Takeda's High-Dose Tetravalent Dengue Vaccine Candidate (HD-TDV)

• Registration Number: NCT02425098
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study is to assess the post-vaccination neutralizing antibody response against each dengue serotype by vaccine group.

Detailed Description

The vaccine being tested in this study was Takeda's Tetravalent Dengue Vaccine Candidate (TDV). TDV is being tested to protect people against dengue fever. This study looked at safety and the titers of antibodies to dengue fever induced in people who were administered a high-dose of TDV (HD-TDV) compared to TDV.

The study enrolled 351 patients. Before being assigned to a treatment group participants were screened for previous exposure to the dengue virus using a Dengue immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA). Participants were randomly assigned in 1:1 ratio (by chance) to one of the two treatment groups-which remained undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* HD-TDV 0.5 mL subcutaneous injection

* TDV 0.5 mL subcutaneous injection

All participants received a single injection on Day 1. Participants were asked to record any symptoms that may or may not be related to the vaccine or the injection site in a diary card for 28 days after vaccination.

This multi-center trial was conducted in Singapore. The overall time of participation in this study was 12 months. Participants made multiple visits to the clinic, including a final visit 1 year after receiving their dose of TDV.

Study Timeline

• Study First Submitted: 2015-04-09
• Study First Submitted QC: 2015-04-20
• Study First Posted: 2015-04-23
• Study Start: 2015-06-03
• Primary Completion: 2017-09-18
• Study Completion: 2017-09-18
• Results First Submitted: 2019-04-10
• Status Verified: 2019-07
• Results First Submitted QC: 2019-07-16
• Last Update Submitted: 2019-07-16
• Results First Posted: 2019-08-28
• Last Update Posted: 2019-08-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 351

Inclusion Criteria

1. Participant signs and dates a written informed consent form where applicable, and any required privacy authorization prior to the initiation of any trial procedures, after the nature of the trial has been explained according to local regulatory requirements.
2. Is aged 21 to 45 years of age, inclusive.
3. Is in good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs) and clinical judgment of the Investigator.
4. Can comply with trial procedures and are available for the duration of follow-up.
5. Has self-declared as never having been vaccinated against Yellow Fever or Japanese Encephalitis Virus.

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Exclusion Criteria

1. Has febrile illness (temperature ≥38°C or ≥100.4°F) or moderate or severe acute illness or infection at the time of enrollment.

2. Has history or any illness that, in the opinion of the Investigator, might interfere with the results of the trial or pose an additional risk to the participant due to participation in the trial, including but not limited to:

   1. Known hypersensitivity or allergy to any of the vaccine components.

   2. Female participants who are pregnant or breastfeeding.

   3. Individuals with any serious chronic or progressive disease according to judgment of the Investigator (e.g. neoplasm, insulin-dependent diabetes, cardiac, renal or hepatic disease, neurologic or seizure disorder or Guillain-Barré syndrome).

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

      • i. 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).
      • ii. 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).
      • iii. Administration of immunoglobulins and/or any blood products within the 3 months prior to Day 1 (Month 0) or planned administration during the trial.
      • iv. Receipt of immunostimulants within 60 days prior to Day 1(Month 0).
      • v. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months prior to Day 1 (Month 0).
      • vi. Human immunodeficiency virus (HIV) infection and HIV-related diseases.
      • vii. Hepatitis C virus (HCV) infection.
      • viii. Genetic immunodeficiency.

3. Has received any other vaccine within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to Day 1 (Month 0) or planning to receive any vaccine within 28 days after Day 1 (Month 0).

4. Has participated in any clinical trial with another investigational product 30 days prior to Day 1 (Month 0) or intent to participate in another clinical trial at any time during the conduct of this trial.

5. Has previously participated in any clinical trial of a dengue candidate vaccine, or previous receipt of a dengue vaccine.

6. Is first-degree relative of individuals involved in trial conduct.

7. For females of childbearing potential who are sexually active, and who have not used any of the acceptable contraceptive methods for at least 2 months prior to Day 1 (Month 0).

   1. Of childbearing potential is defined as status post onset of menarche and not meeting any of the following conditions: bilateral tubal ligation (at least 1 year previously), bilateral oophorectomy (at least 1 year previously) or hysterectomy.

   2. Acceptable birth control methods are defined as one or more of the following:

      • i. Hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring).
      • ii. Barrier (condom with spermicide or diaphragm with spermicide) each and every time during intercourse.
      • iii. Intrauterine device (IUD).
      • iv. Monogamous relationship with vasectomized partner (partner must have been vasectomized for at least six months prior to Day 1 [Month 0]).

8. Females of childbearing potential who are sexually active, and who refuse to use an acceptable contraceptive method from signing the informed consent up to 6 weeks post-vaccination.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tetravalent Dengue Vaccine (TDV)	Takeda's Tetravalent Dengue Vaccine Candidate (TDV)	Tetravalent Dengue Vaccine \[TDV\], 0.5 mL, subcutaneous injection on Day 1. TDV comprised one molecularly-characterized and cloned TDV-2 live attenuated dengue virus strain and three recombinant live attenuated dengue virus strains: TDV-1, TDV-3 and TDV-4. TDV contained 2\*10\^4 plaque forming units (PFU), 5\*10\^3 PFU, 1\*10\^5 PFU, and 3\*10\^5 PFU of TDV-1, TDV-2, TDV-3 and TDV-4 respectively.
High-dose Tetravalent Dengue Vaccine (HD-TDV)	Takeda's High-Dose Tetravalent Dengue Vaccine Candidate (HD-TDV)	High-dose Tetravalent Dengue Vaccine \[HD-TDV\], 0.5 mL, subcutaneous injection on Day 1. TDV comprised one molecularly-characterized and cloned TDV-2 live attenuated dengue virus strain and three recombinant live attenuated dengue virus strains: TDV-1, TDV-3 and TDV-4. TDV contained 2\*10\^4 plaque forming units (PFU), 5\*10\^4 PFU, 1\*10\^5 PFU, and 3\*10\^5 PFU of TDV-1, TDV-2, TDV-3 and TDV-4 respectively.

Primary Outcome Measures

Name	Time	Method
Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 180	Day 180	GMTs were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT.
Seropositivity Rate for Each of the Four Dengue Serotypes at Day 180	Day 180	Seropositivity rate was defined as the percentage of participants being seropositive, derived from titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10 (for each serotype). Seropositivity rates were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4.
Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 15	Day 15	GMTs were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by microneutralization test \[MNT\].
Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 90	Day 90	GMTs were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT.
Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 365	Day 365	GMTs were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT.
Seropositivity Rate for Each of the Four Dengue Serotypes at Day 30	Day 30	Seropositivity rate was defined as the percentage of participants being seropositive, derived from titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10 (for each serotype). Seropositivity rates were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4.
Seropositivity Rate for Each of the Four Dengue Serotypes at Day 90	Day 90	Seropositivity rate was defined as the percentage of participants being seropositive, derived from titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10 (for each serotype). Seropositivity rates were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4.
Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 30	Day 30	GMTs were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT.
Seropositivity Rate for Each of the Four Dengue Serotypes at Day 15	Day 15	Seropositivity rate was defined as the percentage of participants being seropositive, derived from titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10 (for each serotype). Seropositivity rates were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4.
Seropositivity Rate for Each of the Four Dengue Serotypes at Day 365	Day 365	Seropositivity rate was defined as the percentage of participants being seropositive, derived from titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10 (for each serotype). Seropositivity rates were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary Recorded) Following Vaccination by Severity	Within 7 days after Vaccination	Solicited local 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 \[Grade 0 (\<25 mm), 1 (25 - ≤ 50 mm), 2 (\>50 - ≤ 100 mm), 3 (\> 100 mm)\] and swelling \[Grade 0 (\<25 mm), 1 (25 - ≤ 50 mm), 2 (\>50 - ≤ 100 mm), 3 (\> 100 mm)\].
Number of Participants With Serious Adverse Events (SAEs)	From first vaccination through end of study (Day 365)	A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose 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 due to other reasons than the above-mentioned criteria.
Duration of Vaccine Viremia for Each of the Four Vaccine Strains After Vaccination	Days 5, 7, 9, 11, 15, 17, 21 and 30	The duration of vaccine viremia for each vaccine strain was defined as the date when vaccine viremia was last detected (positive result) to date when vaccine viremia was first detected (positive result) + 1 day. It was assessed for each of the four vaccine strains: TDV-1, TDV-2, TDV-3 and TDV-4. Vaccine viral ribonucleic acid (RNA) was detected by reverse transcription-polymerase chain reaction (RT-PCR) assay.
Level of Vaccine Viremia for Each of the Four Vaccine Strains After Vaccination	Days 5, 7, 9, 11, 15, 17, 21 and 30	Vaccine Viremia was assessed for each of the four vaccine strains: TDV-1, TDV-2, TDV-3 and TDV-4. Vaccine viral ribonucleic acid (RNA) was detected by reverse transcription-polymerase chain reaction (RT-PCR) assay.
Number of Participants With at Least One Unsolicited Adverse Events (AEs) Following Vaccination	Within 28 days after 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.
Percentage of Participants Positive for Vaccine Viremia for Each of the Four Vaccine Strains After Vaccination	Days 5, 7, 9, 11, 15, 17, 21 and 30	Vaccine Viremia was assessed for each of the four vaccine strains: TDV-1, TDV-2, TDV-3 and TDV-4. Vaccine viral ribonucleic acid (RNA) was detected by reverse transcription-polymerase chain reaction (RT-PCR) assay.
Number of Participants With Solicited Systemic Adverse Events (AEs) (Diary Recorded) Following Vaccination by Severity	Within 14 days after 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). A systemic AE of fever (defined as ≥ 100.4°F) was derived from a daily temperature reading recorded within 14 days after vaccination.
Geometric Mean Neutralizing Antibody Titers (GMT) for Each of the Four Dengue Serotypes Assessed by Dengue Baseline Seropositivity (MNT) Status	Days 15, 30, 90, 180 and 365	Baseline dengue seropositivity was based on the microneutralization test (MNT) result and was defined as a reciprocal neutralizing titer ≥10 for one or more dengue serotype at baseline. The four DENV serotypes are DENV-1, DENV-2, DENV-3, and DENV-4.
Seropositivity Rate for Each of the Four Dengue Serotypes Assessed by Dengue Baseline Seropositivity (MNT) Status	Days 15, 30, 90, 180, and 365	Baseline dengue seropositivity was based on the MNT result and was defined as a reciprocal neutralizing titer ≥10 for one or more dengue serotype at baseline. Seropositive rate was defined as a reciprocal neutralizing titer ≥ 10. Seropositivity was assessed for the four Dengue serotypes are DENV-1, DENV-2, DENV-3, and DEN-4.

Trial Locations

Locations (3)

Changi General Hospital; 🇸🇬 Singapore, Singapore

Tan Tock Seng Hospital; 🇸🇬 Singapore, Singapore

Singapore General Hospital; 🇸🇬 Singapore, Singapore