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

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ClinicalTrials.gov Identifier: NCT01511250
Recruitment Status : Completed
First Posted : January 18, 2012
Results First Posted : March 27, 2018
Last Update Posted : March 27, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Healthy Biological: TDV Biological: Placebo Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 360 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: 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
Actual Study Start Date : November 16, 2011
Actual Primary Completion Date : April 1, 2016
Actual Study Completion Date : April 15, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dengue
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Part I: TDV 21 to 45 Years (yrs)
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
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.
Placebo Comparator: Part I: Placebo 21 to 45 yrs
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Biological: Placebo
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Experimental: Part I: TDV 12 to 20 yrs
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
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.
Placebo Comparator: Part I: Placebo 12 to 20 yrs
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Biological: Placebo
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Experimental: Part I: TDV 6 to 11 yrs
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
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.
Placebo Comparator: Part I: Placebo 6 to 11 yrs
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Biological: Placebo
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Experimental: Part I: TDV 1.5 to 5 yrs
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
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.
Placebo Comparator: Part I: Placebo 1.5 to 5 yrs
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Biological: Placebo
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Experimental: Part II: TDV 1.5 to 11 yrs
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
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.
Placebo Comparator: Part II: Placebo 1.5 to 11 yrs
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Biological: Placebo
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).



Primary Outcome Measures :
  1. Number of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination Dose by Severity [ Time Frame: Within 14 days after either of the vaccination given on Day 0 or 90 (Day 14 for first vaccination, Day 104 for second vaccination) ]
    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).

  2. Number of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (In Clinic Assessment) Following Either Vaccination Dose by Severity [ Time Frame: Within 28 days after either of the vaccination given on Day 0 or 90 (Day 28 for first vaccination, Day 118 for second vaccination) ]
    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).

  3. Number of Participants With Solicited Systemic Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination Dose by Severity [ Time Frame: Within 14 days after either of the vaccination given on Day 0 or 90 (Day 14 for first vaccination, Day 104 for second vaccination) ]
    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.

  4. Number of Participants With Any Solicited AE Following Either Vaccination Dose [ Time Frame: Within 14 days after either of the vaccination given on Day 0 or 90 (Day 14 for first vaccination, Day 104 for second vaccination) ]
    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.

  5. Number of Participants With at Least One Unsolicited AE Following Either Vaccination Dose by Severity [ Time Frame: Unsolicited AEs were collected within 28 days of all vaccinations. Serious AEs were collected throughout the study up to Day 1080 ]
    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.

  6. Seropositivity Rate to Each of the Four Dengue Serotypes at Day 120 [ Time Frame: 30 days after second vaccination (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.


Secondary Outcome Measures :
  1. Part I: Number of Participants Positive for Vaccine Viremia for Each of Four Vaccine Strain Serotypes After the Each Vaccination [ Time Frame: Days 0, 7, 14, 90, 97, and 104 ]
    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.

  2. Part I: Duration of Vaccine Viremia [ Time Frame: Days 0, 7, 14, 90, 97, and 104 ]
  3. Part I: Titers of Vaccine Viremia [ Time Frame: Days 0, 7, 14, 90, 97, and 104 ]
  4. Seropositivity Rate to Each of the Four Dengue Serotypes [ Time Frame: Day 28 and Day 90 (Parts 1 and 2) and Days 180, 360, 720 and 1080 in Part 1 ]
    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.

  5. Seroconversion Rate to Each of the Four Dengue Serotypes [ Time Frame: Day 28, 90 and 120 (Parts 1 and 2) and Days 180, 360, 720 and 1080 in Part 1 ]
    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.

  6. Geometric Mean Neutralizing Antibody Titers (GMTs) of All Four Dengue Serotypes [ Time Frame: Day 28, 90 and 120 (Parts 1 and 2) and Days 180, 360, 720 and 1080 in Part 1 ]
    GMTs were assessed for the four dengue serotypes: TDV-1, TDV-2, TDV-3, and TDV-4.

  7. Geometric Mean Fold Rise (GMFR) of Dengue Neutralizing Antibody Titers for Each of the 4 Dengue Serotypes [ Time Frame: Day 28 and Day 90 (Parts 1 and 2) and Days 120, 180, 360, 720 and 1080 in Part 1 ]
  8. Number of Participants With Confirmed Dengue Fever [ Time Frame: Day 1 to Day 1080 ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Months to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01511250


Locations
Colombia
Program For The Study and Control of Tropical Diseases
Medellin, Colombia
Puerto Rico
Ponce School of Medicine, CAIMED Center
Ponce, Puerto Rico, 716
University of Puerto Rico School of Medicine
San Juan, Puerto Rico, 00935
Latin Clinical Trial Center
San Juan, Puerto Rico, 909
Singapore
National University Hospital
Singapore, Singapore, 119228
Changi General Hospital
Singapore, Singapore, 529889
Thailand
Faculty of Tropical Medicine, Mahidol University
Bangkok, Thailand, 10400
Phramongkutklao Hospital
Bangkok, Thailand, 10400
Sponsors and Collaborators
Takeda
Investigators
Study Director: Medical Director Clinical Science Takeda

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01511250     History of Changes
Other Study ID Numbers: INV-DEN-203
First Posted: January 18, 2012    Key Record Dates
Results First Posted: March 27, 2018
Last Update Posted: March 27, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda:
Normal healthy adults and children
Safety and tolerability
Active vaccine
Placebo
Dengue virus vaccine
Immune response

Additional relevant MeSH terms:
Dengue
Arbovirus Infections
Virus Diseases
Flavivirus Infections
Flaviviridae Infections
RNA Virus Infections
Hemorrhagic Fevers, Viral
Vaccines
Immunologic Factors
Physiological Effects of Drugs