A Phase II Trial of a Live Attenuated Virus Tetravalent Dengue Vaccine in Healthy Adults in Thailand

Study Overview
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Brief Summary
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This descriptive study will evaluate the safety and immunogenicity of different formulations of the WRAIR dengue vaccine compared to a placebo.

Detailed Description
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Subjects will be randomized into one of three groups. One group will receive a placebo vaccine and the other two will receive different dengue vaccine formations. Each subject will receive two doses six months apart. All subjects will have 11 venipunctures during 11 visits (i.e., screening plus 10 study visits) over a period of nine months.

Official Title
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Phase II, Randomized, Double-blind, Single Center, Controlled Study of Two Doses of Different Formulations of the WRAIR Live Attenuated Tetravalent Dengue Vaccine Compared to a Placebo Control, Administered on a 0-6 Month Schedule, to Healthy Adults

Conditions
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Dengue

Intervention / Treatment
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* Biological: T-DEN F17
* Biological: T-DEN F-19
* Other: Placebo Comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A healthy male or female adult 20-25 years of age (≥20 years of age and ≤25 years of age) at the time of vaccination; Free of obvious health problems as established by medical history and physical examination before entering into the study; Written informed consent obtained from the subject; Able to read the Subject Information Sheet and Consent Form; Subjects who the investigator believes can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits) should be enrolled in the study; females must be of non-childbearing potential, i.e. surgically sterilized or, if of childbearing potential, she must be abstinent or on adequate contraceptive precautions (i.e. intrauterine contraceptive device; oral contraceptives or other equivalent hormonal contraception, e.g. progestin implantable, cutaneous hormonal patch or injectable contraceptives) for 30 days prior to vaccination, have a negative pregnancy test within 48 hours prior to vaccination and must agree to continue such precautions for 60 days after completion of the vaccination series Exclusion Criteria: Pregnant or lactating female, planning to become pregnant or planning to discontinue abstinence or contraceptive precautions; History of any neurological or behavioral disorder or seizures, with the exception of a single febrile seizure in childhood; History of drug abuse or alcohol consumption (more than 2 drinks per day); History of allergic disease/reaction likely to be exacerbated by any component of the vaccine; Acute or chronic, pulmonary, cardiovascular, hepatic, renal, hematologic or endocrine functional defect, as determined by physical examination or laboratory tests; Any confirmed or suspected immunosuppressive or immunodeficient condition or seropositive for HBsAg, anti-HCV or anti-HIV; Acute disease at the time of enrollment (acute disease is defined as the presence of a moderate or severe illness with or without fever); Chronic hepatomegaly, right upper quadrant abdominal pain or tenderness; Chronic splenomegaly, left upper quadrant abdominal pain or tenderness; Hypertension; chest pain, palpitations, dizziness, shortness of breath, arrhythmias or friction rubs; Use of any investigational or non-registered drug or vaccine other than the study vaccine within 30 days preceding the study vaccine (includes placebo) or planned use during the study period; Planned administration of a vaccine not foreseen by the study protocol during the period starting from 30 days before the first dose of the study vaccine/placebo and ending 30 days after the second dose; A planned move to a location that will prohibit participating in the trial for 9 months after the initial vaccination; Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within 90 days preceding the first dose or planned administration during the study period. For corticosteroids, this will mean prednisone, or equivalent, 0.5 mg/kg/day. Inhaled and topical steroids are allowed; Administration of immunoglobulins and/or blood products within 90 days preceding the first dose or planned administration during the study period; Any chronic systemic drug therapy to be continued during the study period (except for vitamin/mineral supplements or routine treatment for gastro-esophageal reflux); No easy access to a fixed or mobile telephone

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 25 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-DEN F17<br>Full Dose (0.5 mL) 0 and 6 months | Biological: T-DEN F17<br>* A single dose of 0.5 mL of the dengue vaccine was injected subcutaneously into the upper-outer triceps/deltoid area of the non-dominant arm at Day 0 and at 6 months.<br>* Other names: T-DEN vaccine;|
| Experimental: T-DEN F19<br>Full Dose (0.5 mL) at 0 and 6 months | Biological: T-DEN F-19<br>* A single dose of 0.5 mL of the dengue vaccine was injected subcutaneously into the upper-outer triceps/deltoid area of the non-dominant arm at Day 0 and at 6 months.<br>|
| Placebo Comparator: Placebo Comparator<br>0.5 mL sterile buffer at 0 and 6, subcutaneous injection | Other: Placebo Comparator<br>* A single dose of 0.5 mL of the placebo sterile solution of buffer identical in appearance to vaccine)was injected subcutaneously into the upper-outer triceps/deltoid area of the non-dominant arm at Day 0 and at 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Any Grade 3 Solicited Adverse Events (AEs) Within 21 Days Follow-up After Dose 1 | Percentage of subjects with any grade 3 adverse events (AEs) within 21 days follow-up after dose 1 (0 month) | 0-21 days after dose 1 | 
| Neutralizing Antibody Geometric Mean Titer (GMT) to DEN Types 1, 2, 3 and 4; 30 and 90 Days After Dose 2 | Neutralizing antibody geometric mean titer (GMT) to DEN types 1, 2, 3 and 4 will be measured 30 and 90 days following the administration of the 2nd dose (6 month) | 30 and 90 days after dose 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects With Any Adverse Events (AEs) Within 21 Days Follow-up After Dose 2 of Study Vaccine | Percentage of subjects with any adverse events (AEs) solicited and unsolicited reported during the 21-day post-vaccination period following dose 2 | 0-21 days after dose 2 of study vaccine | 
| Incidence of Unsolicited AEs Within 31 Days (Days 0-30) After Any Study Vaccine Dose | Incidence of unsolicited AEs reported within the 31-day (Days 0-30) post-vaccination period for each study vaccine | 0-30 days after each study vaccine dose | 
| Incidence of Serious Adverse Events (SAEs) Throughout the Entire Study Period | Number of subjects experiencing serious adverse events (SAEs) throughout the entire 9 month study period | 9 months | 
| Laboratory Values Above the Alert Values Within 31 Days (Days 0-30) After Each Vaccine Dose | Laboratory valuesabove the alert values within 31 days (days 0-30) after each vaccine dose. Change from baseline in hematological and biochemical levels with respect to normal ranges. PI(D2, 5, 8, 12) = Post Dose 1, Days 2, 5, 8 and 12 PI(D5, 12,14) = Post Dose 1, Days 5, 12 and 14 PI(M1) = Post Dose 1, Month 1 PI(M6) = Post Dose 1, Month 6 PII(D2, 5, 8, 12) = Post Dose 2, Days 2, 5, 8 and 12 PII(D5, 8, 12, 14) = Post Dose 2, Days 5, 8, 12 and 14 PII(M7) = Post Dose 2, Month 7 | within 31 days after each vaccine dose | 
| Incidence of Abnormal Findings at DEN Physical Examination After Each Vaccine Dose | Incidence of abnormal dengue examination findings reported during the 31-Day (Days 0-30) post-vaccination period, per dose | 31 days post-vaccination per dose | 
| Incidence of Suspected and Confirmed Dengue Throughout the Entire Study Period. | Number of subjects with incidence of suspected and confirmed dengue throughout the entire study period. | 9 months | 
| Percentage of Subjects With Neutralizing Antibodies to Each DEN Type, After Each Dose of Study Vaccines | Percentage of subject with Tetravalent responses for neutralizing antibodies, according to pre-vaccination dengue immune status. There was no placebo run for DEN Monovalent. PRE = Pre-vaccination PI(M1) = Post Dose 1, Month 1 PII(M7) = Post Dose 2, Month 7 | post dose 1 and 2 | 
| Neutralizing Antibody Sero-response to Each DEN Type (Increase Neut.) Antibody From pre-to Post-vaccination, to be Determined by a Qualified Assay) After Each Dose of Study Vaccines | Seropositivity rates for neut. antibodies according to pre-vaccination flavivirus immune status-primed/unprimed subjects. PRE = Pre-vaccination PI(M1) = Post Dose 1, Month 1 PII(M7) = Post Dose 2, Month 7 PII(M9) = Post Dose 2, Month 9 | 9 months | 
| Incidence of Measurable Dengue Viremia at Specified Time Points After Each Dose | Percentage of subjects with incidence of measurable dengue viremia at specified time points after each dose. Negative = GEQ/uL results is equal to zero Undetermined = GEQ/uL result is below LOD Positive = GEQ/uL result is >=LOD Missing = No data PI(M1) = Post Dose 1, Month 1 PII(D2,5,8,12) = Post Dose 2, Days 2, 5,8 and 12 PII(D5,8,12,14) = Post Dose 2, Days 5, 8, 12 and 14 PII(M7) = Post Dose 2, Month 7 | within 7 months |