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A Two-dose Primary Vaccination Study of a Tetravalent Dengue Virus Purified Inactivated Vaccine vs. Placebo in Healthy Adults (DPIV-001)

Primary Purpose

Dengue Fever

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
4 µg TDENV-PIV with Alum adjuvant
1 µg TDENV-PIV with AS03B1 adjuvant
Phosphate buffered saline
1 µg TDENV-PIV with Alum adjuvant
1 µg TDENV-PIV with AS01E1 adjuvant
Sponsored by
U.S. Army Medical Research and Development Command
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Dengue Fever focused on measuring Dengue, Dengue fever, Dengue Hemorrhagic Fever, Flavivirus

Eligibility Criteria

18 Years - 39 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • 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, etc.)
  • A male or female between 18 and 39 years of age (inclusive) at the time of consent
  • Written informed consent obtained from the subject
  • Healthy subjects as established by medical history and clinical examination before entering into the study
  • Female subjects of non-childbearing potential (non-childbearing potential is defined as having either a current tubal ligation at least three months prior to enrollment, hysterectomy, ovariectomy, or is post-menopause). See Definition of Terms for adequate contraception.
  • Female subjects of childbearing potential may be enrolled in the study, if the subject has:

    • Practiced adequate contraception for 30 days prior to vaccination, and
    • A negative urine pregnancy test on the day of vaccination, and
    • Agreed to continue adequate contraception until two months after completion of the vaccination series

Exclusion Criteria:

  • Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines/placebo during the period starting 30 days preceding the first dose of study vaccine/placebo and/or planned use during the study period
  • Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting 180 days prior to the first vaccine/placebo dose (for corticosteroids, this will mean prednisone ≥ 20 mg/day or equivalent; inhaled and topical steroids are allowed)
  • Planned administration or administration of a vaccine/product not foreseen by the study protocol during the period starting 30 days prior to the first dose of vaccine/placebo until after the visit at Day 56 (if influenza activity warrants vaccination of healthy young adults, influenza vaccination will be encouraged and will not lead to study exclusion)
  • Planned administration of any flavivirus vaccine for the entire study duration
  • Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device).
  • Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
  • Family history of congenital or hereditary immunodeficiency
  • History of, or current auto-immune disease
  • History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine/placebo or related to a study procedure
  • Major congenital defects or serious chronic illness
  • History of any neurological disorders or seizures
  • Acute disease and/or fever (≥37.5°C/99.5°F oral body temperature) at the time of enrollment (a subject with a minor illness, i.e., mild diarrhea, mild upper respiratory infection, etc., without fever, may be enrolled at the discretion of the investigator)
  • Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality,as determined by physical examination or laboratory screening tests
  • Administration of immunoglobulins and/or any blood products during the period starting 90 days preceding the first dose of study vaccine/placebo or planned administration during the study period
  • History of chronic alcohol consumption and/or drug abuse
  • Pregnant or lactating female or female planning to become pregnant or planning to discontinue contraceptive precautions
  • A planned move to a location that will prohibit participating in the trial until study end for the participant
  • Any other condition which, in the opinion of the investigator, prevents the subject from participating in the study.
  • Subject seropositive for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (anti-HCV), or human immunodeficiency virus antibodies (anti-HIV)
  • Safety laboratory test results that are outside the acceptable values at screening. The following values are not acceptable:

    • >110% upper limit of normal (ULN) for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, creatinine, serum urea nitrogen (SUN) and bilirubin (total and direct)
    • <100% lower limit of normal (LLN) or > 120% ULN for hemoglobin, hematocrit and platelet count
    • <75% LLN or >110% ULN for total white blood cell count (WBC) Note that all screening laboratory results must be either within normal limits (WNL) or no more than Grade l not clinically significant (NCS)

(LLN=lower limit of normal; ULN= upper limit of normal, WNL= within normal limits, NCS= not clinically significant)

Sites / Locations

  • WRAIR, Clinical Trials Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Experimental

Arm Label

TDENV-PIV alum4

TDENV-PIV AS01E1

TDENV-PIV AS03B1

Placebo

TDENV-PIV alum1

Arm Description

4 µg TDENV-PIV with Alum adjuvant; 0.5 mL intramuscular injection at 0 and 28 days

1 µg TDENV-PIV with AS01E1 adjuvant; 0.5 mL intramuscular injection at 0 and 28 days

1 µg TDENV-PIV with AS03B1 adjuvant; 0.5 mL intramuscular injection at 0 and 28 days

Phosphate buffered saline; 0.5 mL intramuscular injection at 0 and 28 days

1 µg TDENV-PIV with Alum adjuvant; 0.5 mL intramuscular injection at 0 and 28 days

Outcomes

Primary Outcome Measures

Number of Subjects With Adverse Events Within the 28 Day Follow-up
Number of subjects with adverse events occurring within days 0-28 following vaccination
Incidence of Any Symptoms (Solicited and Unsolicited) Reported During the 7-day Post Vaccination Period. Total Vaccinated Cohort (TVC)
Overall incidence of any symptoms (solicited and unsolicited) reported during the 7-day (days 0-6) post vaccination period in TVC population
Incidence of General Symptoms (Solicited and Unsolicited) Reported During the 7-day Post Vaccination Period, Total Vaccinated Cohort (TVC)
Incidence of General Symptoms (Solicited and Unsolicited) Reported during the 7-day Post Vaccination Period for TVC population. General symptoms are described as fatigue, gastrointestinal symptoms, headache, joint pain, muscle aches and increased temperature (oral).
Incidence of Local Symptoms (Solicited and Unsolicited) Reported During the 7-day Post Vaccination Period, Total Vaccinated Cohort (TVC)
Incidence of Local Symptoms (Solicited and Unsolicited) Reported during the 7-day Post Vaccination Period in TVC population. Local symptoms are described as pain, redness and swelling.
Summary of Subjects With Serious Adverse Events
Summary of subjects with serious adverse events through out the study

Secondary Outcome Measures

Number of Subjects With Laboratory Values Within and Outside the Normal Ranges and With Different Grade of Adverse Event From Screening to Day 56 Visit
The percentage of subjects with hematological and biochemical laboratory values within and outside the normal ranges and with different grade of AE were tabulated with exact 95% CI at baseline and at each specified timepoint. Safety laboratory assays were performed at a WRAIR-designated Clinical Laboratory Improvement Amendments-certified laboratory. All safety-related clinical laboratory values were reviewed and all abnormal values were assessed by the investigators as clinically significant or not, with respect to safety. PRE = Pre-vaccination, Day 0 visit PI(D7) = Post-dose 1, Day 7 visit PI(D28) = Post-dose 1, Day 28 visit PII(D35) = Post-dose 2, Day 35 visit PII(D56) = Post-dose 2, Day 56 visit PII(M4) = Post-dose 2, Month 4 visit PII(M7) = Post-dose 2, Month 7 visit PII(M10) = Post-dose 2, Month 10 visit PII(M13) = Post-dose 2, Month 13 visit
Geometric Mean Titers (GMTs) of Neutralizing Antibody Titers Specific to Each DENV Type - According to Protocol Population (ATP)
Geometric Mean Titers (GMTs) of Neutralizing antibody titers specific to each DENV type were measured by a quantitative microneutralization assay with a titer giving 50% reduction in viral infection (MN50) at specified time points. MN50 is specific and sensitive for the detection of anti-DENV neutralizing antibodies. The cut-off for seropositivity was 1: 10 for neutralizing antibody titers measured by MN50 assay. MN50 assay was used to determine initial DENV antibody status of subjects for inclusion in the ATP cohort. PRE = Pre-vaccination, Day 0 visit PI(D7) = Post-dose 1, Day 7 visit PI(D28) = Post-dose 1, Day 28 visit PII(D56) = Post-dose 2, Day 56 visit PII(M4) = Post-dose 2, Month 4 visit PII(M7) = Post-dose 2, Month 7 visit PII(M10) = Post-dose 2, Month 10 visit PII(M13) = Post-dose 2, Month 13 visit
Number of Subject Showing Monovalent, Bivalent, Trivalent and Tetravalent Response for Neutralizing Antibodies - Total Vaccinated Cohort (TVC)
Number of subjects showing Monovalent, bivalent, trivalent and tetravalent response for neutralizing antibodies by Microneutralization Titer (giving 50% reduction in viral infection (MN50)) in the TVC population. PI(D7) = Post-dose 1, Day 7 visit PI(D28) = Post-dose 1, Day 28 visit PII(D56) = Post-dose 2, Day 56 visit PII(M4) = Post-dose 2, Month 4 visit PII(M7) = Post-dose 2, Month 7 visit PII(M10) = Post-dose 2, Month 10 visit PII(M13) = Post-dose 2, Month 13 visit

Full Information

First Posted
August 8, 2012
Last Updated
August 8, 2018
Sponsor
U.S. Army Medical Research and Development Command
Collaborators
GlaxoSmithKline, Walter Reed Army Institute of Research (WRAIR)
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1. Study Identification

Unique Protocol Identification Number
NCT01666652
Brief Title
A Two-dose Primary Vaccination Study of a Tetravalent Dengue Virus Purified Inactivated Vaccine vs. Placebo in Healthy Adults
Acronym
DPIV-001
Official Title
A Phase I, Randomized, Placebo-Controlled, Observer-blind, Two-dose (0-28 Day Schedule) Primary Vaccination Study of Walter Reed Army Institute of Research (WRAIR) Tetravalent Dengue Virus Purified Inactivated Vaccine (TDENV-PIV) in Healthy Adults in a Non-Endemic Region
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
September 2012 (Actual)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
November 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
U.S. Army Medical Research and Development Command
Collaborators
GlaxoSmithKline, Walter Reed Army Institute of Research (WRAIR)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The study is designed to afford a safety and immunogenicity assessment of three Tetravalent Dengue Virus-Purified Inactivated Vaccine(TDENV-PIV) vaccine candidates.
Detailed Description
The study is designed to afford a safety and immunogenicity assessment of three Tetravalent Dengue Virus-Purified Inactivated Vaccine(TDENV-PIV) vaccine candidates, each formulated with a different adjuvant: either aluminum hydroxide, AS01E or AS03B (adjuvants used in Glaxo Smith Kline (GSK) Biologicals' hepatitis B candidate vaccine, malaria candidate vaccine and pandemic flu vaccine, respectively). Each vaccine candidate will contain 1 µg of purified virus antigen per each of the four DENV types. Additionally, the study will evaluate an alum adjuvanted TDENV-PIV vaccine candidate containing 4 µg of purified virus antigen per each of the four DENV types. The control group will receive a saline placebo. All experimental vaccinations will be administered according to a 2-dose schedule, 28 days apart.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dengue Fever
Keywords
Dengue, Dengue fever, Dengue Hemorrhagic Fever, Flavivirus

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
100 (Actual)

8. Arms, Groups, and Interventions

Arm Title
TDENV-PIV alum4
Arm Type
Experimental
Arm Description
4 µg TDENV-PIV with Alum adjuvant; 0.5 mL intramuscular injection at 0 and 28 days
Arm Title
TDENV-PIV AS01E1
Arm Type
Experimental
Arm Description
1 µg TDENV-PIV with AS01E1 adjuvant; 0.5 mL intramuscular injection at 0 and 28 days
Arm Title
TDENV-PIV AS03B1
Arm Type
Experimental
Arm Description
1 µg TDENV-PIV with AS03B1 adjuvant; 0.5 mL intramuscular injection at 0 and 28 days
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Phosphate buffered saline; 0.5 mL intramuscular injection at 0 and 28 days
Arm Title
TDENV-PIV alum1
Arm Type
Experimental
Arm Description
1 µg TDENV-PIV with Alum adjuvant; 0.5 mL intramuscular injection at 0 and 28 days
Intervention Type
Biological
Intervention Name(s)
4 µg TDENV-PIV with Alum adjuvant
Intervention Type
Biological
Intervention Name(s)
1 µg TDENV-PIV with AS03B1 adjuvant
Intervention Type
Other
Intervention Name(s)
Phosphate buffered saline
Intervention Type
Biological
Intervention Name(s)
1 µg TDENV-PIV with Alum adjuvant
Intervention Type
Biological
Intervention Name(s)
1 µg TDENV-PIV with AS01E1 adjuvant
Primary Outcome Measure Information:
Title
Number of Subjects With Adverse Events Within the 28 Day Follow-up
Description
Number of subjects with adverse events occurring within days 0-28 following vaccination
Time Frame
Days 0-28
Title
Incidence of Any Symptoms (Solicited and Unsolicited) Reported During the 7-day Post Vaccination Period. Total Vaccinated Cohort (TVC)
Description
Overall incidence of any symptoms (solicited and unsolicited) reported during the 7-day (days 0-6) post vaccination period in TVC population
Time Frame
Days 0-6 post vaccination
Title
Incidence of General Symptoms (Solicited and Unsolicited) Reported During the 7-day Post Vaccination Period, Total Vaccinated Cohort (TVC)
Description
Incidence of General Symptoms (Solicited and Unsolicited) Reported during the 7-day Post Vaccination Period for TVC population. General symptoms are described as fatigue, gastrointestinal symptoms, headache, joint pain, muscle aches and increased temperature (oral).
Time Frame
Days 0-6 post vaccination
Title
Incidence of Local Symptoms (Solicited and Unsolicited) Reported During the 7-day Post Vaccination Period, Total Vaccinated Cohort (TVC)
Description
Incidence of Local Symptoms (Solicited and Unsolicited) Reported during the 7-day Post Vaccination Period in TVC population. Local symptoms are described as pain, redness and swelling.
Time Frame
Days 0-6 post vaccination
Title
Summary of Subjects With Serious Adverse Events
Description
Summary of subjects with serious adverse events through out the study
Time Frame
days 0-392
Secondary Outcome Measure Information:
Title
Number of Subjects With Laboratory Values Within and Outside the Normal Ranges and With Different Grade of Adverse Event From Screening to Day 56 Visit
Description
The percentage of subjects with hematological and biochemical laboratory values within and outside the normal ranges and with different grade of AE were tabulated with exact 95% CI at baseline and at each specified timepoint. Safety laboratory assays were performed at a WRAIR-designated Clinical Laboratory Improvement Amendments-certified laboratory. All safety-related clinical laboratory values were reviewed and all abnormal values were assessed by the investigators as clinically significant or not, with respect to safety. PRE = Pre-vaccination, Day 0 visit PI(D7) = Post-dose 1, Day 7 visit PI(D28) = Post-dose 1, Day 28 visit PII(D35) = Post-dose 2, Day 35 visit PII(D56) = Post-dose 2, Day 56 visit PII(M4) = Post-dose 2, Month 4 visit PII(M7) = Post-dose 2, Month 7 visit PII(M10) = Post-dose 2, Month 10 visit PII(M13) = Post-dose 2, Month 13 visit
Time Frame
day 56 visit
Title
Geometric Mean Titers (GMTs) of Neutralizing Antibody Titers Specific to Each DENV Type - According to Protocol Population (ATP)
Description
Geometric Mean Titers (GMTs) of Neutralizing antibody titers specific to each DENV type were measured by a quantitative microneutralization assay with a titer giving 50% reduction in viral infection (MN50) at specified time points. MN50 is specific and sensitive for the detection of anti-DENV neutralizing antibodies. The cut-off for seropositivity was 1: 10 for neutralizing antibody titers measured by MN50 assay. MN50 assay was used to determine initial DENV antibody status of subjects for inclusion in the ATP cohort. PRE = Pre-vaccination, Day 0 visit PI(D7) = Post-dose 1, Day 7 visit PI(D28) = Post-dose 1, Day 28 visit PII(D56) = Post-dose 2, Day 56 visit PII(M4) = Post-dose 2, Month 4 visit PII(M7) = Post-dose 2, Month 7 visit PII(M10) = Post-dose 2, Month 10 visit PII(M13) = Post-dose 2, Month 13 visit
Time Frame
up to month 13
Title
Number of Subject Showing Monovalent, Bivalent, Trivalent and Tetravalent Response for Neutralizing Antibodies - Total Vaccinated Cohort (TVC)
Description
Number of subjects showing Monovalent, bivalent, trivalent and tetravalent response for neutralizing antibodies by Microneutralization Titer (giving 50% reduction in viral infection (MN50)) in the TVC population. PI(D7) = Post-dose 1, Day 7 visit PI(D28) = Post-dose 1, Day 28 visit PII(D56) = Post-dose 2, Day 56 visit PII(M4) = Post-dose 2, Month 4 visit PII(M7) = Post-dose 2, Month 7 visit PII(M10) = Post-dose 2, Month 10 visit PII(M13) = Post-dose 2, Month 13 visit
Time Frame
up to month 13

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
39 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 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, etc.) A male or female between 18 and 39 years of age (inclusive) at the time of consent Written informed consent obtained from the subject Healthy subjects as established by medical history and clinical examination before entering into the study Female subjects of non-childbearing potential (non-childbearing potential is defined as having either a current tubal ligation at least three months prior to enrollment, hysterectomy, ovariectomy, or is post-menopause). See Definition of Terms for adequate contraception. Female subjects of childbearing potential may be enrolled in the study, if the subject has: Practiced adequate contraception for 30 days prior to vaccination, and A negative urine pregnancy test on the day of vaccination, and Agreed to continue adequate contraception until two months after completion of the vaccination series Exclusion Criteria: Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines/placebo during the period starting 30 days preceding the first dose of study vaccine/placebo and/or planned use during the study period Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting 180 days prior to the first vaccine/placebo dose (for corticosteroids, this will mean prednisone ≥ 20 mg/day or equivalent; inhaled and topical steroids are allowed) Planned administration or administration of a vaccine/product not foreseen by the study protocol during the period starting 30 days prior to the first dose of vaccine/placebo until after the visit at Day 56 (if influenza activity warrants vaccination of healthy young adults, influenza vaccination will be encouraged and will not lead to study exclusion) Planned administration of any flavivirus vaccine for the entire study duration Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). Family history of congenital or hereditary immunodeficiency History of, or current auto-immune disease History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine/placebo or related to a study procedure Major congenital defects or serious chronic illness History of any neurological disorders or seizures Acute disease and/or fever (≥37.5°C/99.5°F oral body temperature) at the time of enrollment (a subject with a minor illness, i.e., mild diarrhea, mild upper respiratory infection, etc., without fever, may be enrolled at the discretion of the investigator) Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality,as determined by physical examination or laboratory screening tests Administration of immunoglobulins and/or any blood products during the period starting 90 days preceding the first dose of study vaccine/placebo or planned administration during the study period History of chronic alcohol consumption and/or drug abuse Pregnant or lactating female or female planning to become pregnant or planning to discontinue contraceptive precautions A planned move to a location that will prohibit participating in the trial until study end for the participant Any other condition which, in the opinion of the investigator, prevents the subject from participating in the study. Subject seropositive for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (anti-HCV), or human immunodeficiency virus antibodies (anti-HIV) Safety laboratory test results that are outside the acceptable values at screening. The following values are not acceptable: >110% upper limit of normal (ULN) for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, creatinine, serum urea nitrogen (SUN) and bilirubin (total and direct) <100% lower limit of normal (LLN) or > 120% ULN for hemoglobin, hematocrit and platelet count <75% LLN or >110% ULN for total white blood cell count (WBC) Note that all screening laboratory results must be either within normal limits (WNL) or no more than Grade l not clinically significant (NCS) (LLN=lower limit of normal; ULN= upper limit of normal, WNL= within normal limits, NCS= not clinically significant)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Leyi Lin, MD
Organizational Affiliation
Walter Reed Army Institute of Research (WRAIR)
Official's Role
Principal Investigator
Facility Information:
Facility Name
WRAIR, Clinical Trials Center
City
Silver Spring
State/Province
Maryland
ZIP/Postal Code
20910-7500
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
28719287
Citation
Schmidt AC, Lin L, Martinez LJ, Ruck RC, Eckels KH, Collard A, De La Barrera R, Paolino KM, Toussaint JF, Lepine E, Innis BL, Jarman RG, Thomas SJ. Phase 1 Randomized Study of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults in the United States. Am J Trop Med Hyg. 2017 Jun;96(6):1325-1337. doi: 10.4269/ajtmh.16-0634.
Results Reference
derived

Learn more about this trial

A Two-dose Primary Vaccination Study of a Tetravalent Dengue Virus Purified Inactivated Vaccine vs. Placebo in Healthy Adults

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