Study to Investigate the Safety and Immunogenicity of a Tetravalent Chimeric Dengue Vaccine in Healthy Volunteers Between the Ages of 1.5 - 45 Years

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety of Takeda's tetravalent dengue vaccine (TDV) (previously DENVax) administered subcutaneously in healthy adults and children. In addition the antibody response to the four dengue virus serotypes will be evaluated.

Detailed Description
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The vaccine tested in this study was tetravalent dengue vaccine (TDV). TDV was tested to assess safety and immunogenicity in healthy adults and children living in dengue endemic countries. The study enrolled 360 healthy participants. The study was conducted in 2 parts, Part 1 - age descending and and Part 2 - expansion - ages 1.5-11 years. Participants were allocated to one of the four age cohorts in Part 1 (21 to 45 years, 12 to 20 years, 6 to 11 years, and 1.5 to 5 years) and expansion age cohort 1.5-11 years in Part 2. Participants were randomized in 2:1 ratio and in 3: 1 ratio in Part 1 and 2 respectively to receive: TDV 0.5 mL SC injection Placebo (inactive solution) - this is a solution that looks like the study drug but has no active ingredient This multi-center trial was conducted worldwide. The overall time to participate in this study was up to 37 months (including screening period). Participants made multiple visits to the clinic including a final visit at Day 1080.

Official Title
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A Double-Blind, Randomized, Placebo-Controlled, Age Descending and Expansion Phase 2 Study to Investigate the Safety and Immunogenicity of a Tetravalent Chimeric Dengue Vaccine in Healthy Volunteers Between the Ages of 1.5 - 45 Years

Conditions
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Healthy

Intervention / Treatment
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* Biological: TDV
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In good health as determined by medical history, physical examination including height and weight Normal safety laboratory values at screening Negative for human immunodeficiency virus-1 (HIV-1) antibodies, Hepatitis C antibodies & Hepatitis B surface antigen Females negative by urine pregnancy test at screening and immediately prior to injection, and were willing to use reliable means of contraception Weight: Within 1.3 times of the upper limit of local normal age-adjusted body mass index (BMI) Exclusion Criteria: For participants ≥12 years, clinically significant electrocardiogram (ECG) findings History of significant dermatologic (skin) disease within last 6 months History of diabetes mellitus History of thymic pathology, thymectomy, myasthenia or any immunodeficiency History of recurring headaches or migraines Hypersensitivity to any vaccine For participants ≥12 years, positive urine screen for cocaine, amphetamines, opiates, or cannabinoids History of alcohol abuse Pregnant or lactating female

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I: TDV 21 to 45 Years (yrs)<br>TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2*10^4 plaque forming units (PFU), 5*10^4 PFU, 1*10^5 PFU, and 3*10^5 PFU respectively, total virus per dose: 4.7*10^5 PFU. | Biological: TDV<br>* TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2*10^4 PFU, 5*10^4 PFU, 1*10^5 PFU, and 3*10^5 PFU respectively, total virus per dose: 4.7*10^5 PFU.<br>|
| Placebo Comparator: Part I: Placebo 21 to 45 yrs<br>TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | Biological: Placebo<br>* TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).<br>|
| Experimental: Part I: TDV 12 to 20 yrs<br>TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2*10^4 PFU, 5*10^4 PFU, 1*10^5 PFU, and 3*10^5 PFU respectively, total virus per dose: 4.7*10^5 PFU. | Biological: TDV<br>* TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2*10^4 PFU, 5*10^4 PFU, 1*10^5 PFU, and 3*10^5 PFU respectively, total virus per dose: 4.7*10^5 PFU.<br>|
| Placebo Comparator: Part I: Placebo 12 to 20 yrs<br>TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | Biological: Placebo<br>* TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).<br>|
| Experimental: Part I: TDV 6 to 11 yrs<br>TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2*10^4 PFU, 5*10^4 PFU, 1*10^5 PFU, and 3*10^5 PFU respectively, total virus per dose: 4.7*10^5 PFU. | Biological: TDV<br>* TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2*10^4 PFU, 5*10^4 PFU, 1*10^5 PFU, and 3*10^5 PFU respectively, total virus per dose: 4.7*10^5 PFU.<br>|
| Placebo Comparator: Part I: Placebo 6 to 11 yrs<br>TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | Biological: Placebo<br>* TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).<br>|
| Experimental: Part I: TDV 1.5 to 5 yrs<br>TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2*10^4 PFU, 5*10^4 PFU, 1*10^5 PFU, and 3*10^5 PFU respectively, total virus per dose: 4.7*10^5 PFU. | Biological: TDV<br>* TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2*10^4 PFU, 5*10^4 PFU, 1*10^5 PFU, and 3*10^5 PFU respectively, total virus per dose: 4.7*10^5 PFU.<br>|
| Placebo Comparator: Part I: Placebo 1.5 to 5 yrs<br>TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | Biological: Placebo<br>* TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).<br>|
| Experimental: Part II: TDV 1.5 to 11 yrs<br>TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2*10^4 PFU, 5*10^4 PFU, 1*10^5 PFU, and 3*10^5 PFU respectively, total virus per dose: 4.7*10^5 PFU. | Biological: TDV<br>* TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2*10^4 PFU, 5*10^4 PFU, 1*10^5 PFU, and 3*10^5 PFU respectively, total virus per dose: 4.7*10^5 PFU.<br>|
| Placebo Comparator: Part II: Placebo 1.5 to 11 yrs<br>TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | Biological: Placebo<br>* TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination Dose by Severity | Solicited local injection site reactions were collected by subject diary and graded based on the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 for pain [Grade 0 (no pain), 1 (mild), 2 (moderate) and 3 (severe)] and itching (pruritus) [Grade 0 (no itching), 1 (mild), 2 (moderate) and 3 (Severe]. Severity grade for redness (erythema) and swelling (edema/induration) were derived from recorded length of the longest diameter measurement using the FDA Guidance for Industry: Toxicity Grading Scale of Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trial were Grade 0 (<2.5 cm), 1 (mild: 2.5-5 cm), 2 (moderate: 5.1-10 cm) and 3 (severe: >10 cm) and Grade 4 (Potentially Life-threatening: necrosis or exfoliative dermatitis). | Within 14 days after either of the vaccination given on Day 0 or 90 (Day 14 for first vaccination, Day 104 for second vaccination) | 
| Number of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (In Clinic Assessment) Following Either Vaccination Dose by Severity | Solicited local injection site reactions were collected by subject diary and graded based on the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 for pain [Grade 0 (no pain), 1 (mild), 2 (moderate) and 3 (severe)] and itching (pruritus) [Grade 0 (no itching), 1 (mild), 2 (moderate) and 3 (Severe]. Severity grade for redness (erythema) and swelling (edema/induration) were derived from recorded length of the longest diameter measurement using the FDA Guidance for Industry: Toxicity Grading Scale of Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trial were Grade 0 (<2.5 cm), 1 (mild: 2.5-5 cm), 2 (moderate: 5.1-10 cm) and 3 (severe: >10 cm) and Grade 4 (Potentially Life-threatening: necrosis or exfoliative dermatitis). | Within 28 days after either of the vaccination given on Day 0 or 90 (Day 28 for first vaccination, Day 118 for second vaccination) | 
| Number of Participants With Solicited Systemic Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination Dose by Severity | Solicited systemic AEs (headache, muscle pain [myalgia], joint pain [arthralgia], eye pain, sensitivity to light [photophobia], tiredness [fatigue], body rash, nausea, were recorded in the participant's-diary along with vomiting [number of times]), and body temperature). Diary-recorded severity grades were based on the Common Terminology Criteria for Adverse Events (CTCAE). Severity grades were: Mild (Grade 1): transient symptoms, discomfort noticed but was easily tolerated by the participant with no interference to normal daily activities. Moderate (Grade 2): marked symptoms, moderate interference with participant's daily activities. Severe (Grade 3): Considerable interference with participant's daily activities. The CTCAE severity grades for fever and vomiting were derived from the diary-recorded measurements of temperature level and number of episodes, respectively. | Within 14 days after either of the vaccination given on Day 0 or 90 (Day 14 for first vaccination, Day 104 for second vaccination) | 
| Number of Participants With Any Solicited AE Following Either Vaccination Dose | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. Solicited local injection site reactions included pain, itching, erythema, edema and solicited systemic AEs include myalgia, arthralgia, eye pain, photophobia, fatigue, body rash, nausea, vomiting, and fever. | Within 14 days after either of the vaccination given on Day 0 or 90 (Day 14 for first vaccination, Day 104 for second vaccination) | 
| Number of Participants With at Least One Unsolicited AE Following Either Vaccination Dose by Severity | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. The severity of all unsolicited AEs was evaluated by the Investigator (using the Common Terminology Criteria for Adverse Events [CTCAE] v4.03) as follows. Mild (Grade 1): Transient symptoms, discomfort noticed but was easily tolerated by the participant with no interference to normal daily activities. Moderate (Grade 2): Marked symptoms, moderate interference with participant's daily activities. Severe (Grade 3): Considerable interference with participant's daily activities. | Unsolicited AEs were collected within 28 days of all vaccinations. Serious AEs were collected throughout the study up to Day 1080 | 
| Seropositivity Rate to Each of the Four Dengue Serotypes at Day 120 | Seropositivity rate, defined as the percentage of participants seropositive, was derived from titers of dengue-neutralizing antibodies. Participants were classified by titer after Day 0 as seropositive or seronegative. Seropositive was defined as a MNT50 titre value of ≥10 for any serotype and seronegative was defined as titre value of less than (<) 10 for all 4 serotypes. Seropositivity was assessed for the four dengue serotypes: TDV-1, TDV-2, TDV-3, TDV-4. | 30 days after second vaccination (Day 120) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Number of Participants Positive for Vaccine Viremia for Each of Four Vaccine Strain Serotypes After the Each Vaccination | Vaccine viremia was assessed for each of the four vaccine strain serotypes: TDV-1, TDV-2, TDV-3 and TDV-4 for Part-1. Vaccine viral ribonucleic acid (RNA) was detected by a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay. | Days 0, 7, 14, 90, 97, and 104 | 
| Part I: Duration of Vaccine Viremia |  | Days 0, 7, 14, 90, 97, and 104 | 
| Part I: Titers of Vaccine Viremia |  | Days 0, 7, 14, 90, 97, and 104 | 
| Seropositivity Rate to Each of the Four Dengue Serotypes | Seropositivity rate, defined as the percentage of participants seropositive, was derived from titers of dengue-neutralizing antibodies. Participants were classified by titer after Day 0 as seropositive or seronegative. Seropositive was defined as a MNT50 titre value of ≥10 and seronegative was defined as titre value of less than (<) 10. Seropositivity was assessed for the four dengue serotypes: TDV-1, TDV-2, TDV-3, TDV-4. | Day 28 and Day 90 (Parts 1 and 2) and Days 180, 360, 720 and 1080 in Part 1 | 
| Seroconversion Rate to Each of the Four Dengue Serotypes | Seroconversion rate was defined as the percentage of participants with microneutralization test 50% (MNT50) titer ≥10 or, if the titer on Day 0 was ≥10, a 4-fold rise in antibody titer. | Day 28, 90 and 120 (Parts 1 and 2) and Days 180, 360, 720 and 1080 in Part 1 | 
| Geometric Mean Neutralizing Antibody Titers (GMTs) of All Four Dengue Serotypes | GMTs were assessed for the four dengue serotypes: TDV-1, TDV-2, TDV-3, and TDV-4. | Day 28, 90 and 120 (Parts 1 and 2) and Days 180, 360, 720 and 1080 in Part 1 | 
| Geometric Mean Fold Rise (GMFR) of Dengue Neutralizing Antibody Titers for Each of the 4 Dengue Serotypes |  | Day 28 and Day 90 (Parts 1 and 2) and Days 120, 180, 360, 720 and 1080 in Part 1 | 
| Number of Participants With Confirmed Dengue Fever | Dengue fever was assessed in participants who had 3 consecutive days of fever >38°C and tested positive for dengue virus by polymerase chain reaction (PCR) analysis. | Day 1 to Day 1080 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Normal healthy adults and children, Safety and tolerability, Active vaccine, Placebo, Dengue virus vaccine, Immune response