A Two-dose Primary Vaccination Study of a Tetravalent Dengue Virus Purified Inactivated Vaccine vs. Placebo in Healthy Adults (in Puerto Rico) (DPIV-002)

Study Description

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Brief Summary:

This is a first time in humans (FTiH) study designed to assess the experimental TDENV-PIV vaccine in a predominantly dengue-primed adult population. The study is designed to afford a first time in humans (FTiH) safety and immunogenicity assessment of three TDENV-PIV vaccine candidates, each formulated with a different adjuvant: either aluminum hydroxide, AS01E or AS03B (adjuvants used in 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. There is a parallel FTiH study that is conducted in the United States in a dengue-naive population using the same investigational vaccines.

Condition or disease	Intervention/treatment	Phase
Dengue Fever	Biological: Biological/Vaccine: 4 µg TDENV-PIV with Alum adjuvant; Biological: Biological/Vaccine: 1 µg TDENV-PIV with AS03B adjuvant; Other: Phosphate buffered saline; Biological: 1 µg TDENV-PIV with Alum adjuvant; Biological: 1 µg TDENV-PIV with AS01E adjuvant	Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	100 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	A Phase I, Randomized, Placebo-Controlled, Observer-blind, Two-dose (0-28 Day Schedule) Primary Vaccination Study of WRAIR Tetravalent Dengue Virus Purified Inactivated Vaccine (TDENV-PIV) in Healthy Adults in Puerto Rico
Actual Study Start Date :	November 2012
Actual Primary Completion Date :	January 20, 2017
Actual Study Completion Date :	March 23, 2017

Arms and Interventions

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Arm	Intervention/treatment
Experimental: TDENV-PIV alum4; 4 µg TDENV-PIV with Alum adjuvant; 0.5 mL intramuscular injection at 0 and 28 days	Biological: Biological/Vaccine: 4 µg TDENV-PIV with Alum adjuvant
Experimental: TDENV-PIV AS03B; 1 µg TDENV-PIV with AS03B adjuvant; 0.5 mL intramuscular injection at 0 and 28 days	Biological: Biological/Vaccine: 1 µg TDENV-PIV with AS03B adjuvant
Placebo Comparator: Placebo; Phosphate buffered saline; 0.5 mL intramuscular injection at 0 and 28 days	Other: Phosphate buffered saline
Experimental: TDENV-PIV alum1; 1 µg TDENV-PIV with Alum adjuvant; 0.5 mL intramuscular injection at 0 and 28 days	Biological: 1 µg TDENV-PIV with Alum adjuvant
Experimental: TDENV-PIV AS01E; 1 µg TDENV-PIV with AS01E adjuvant; 0.5 mL intramuscular injection at 0 and 28 days	Biological: 1 µg TDENV-PIV with AS01E adjuvant

Outcome Measures

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Primary Outcome Measures :

1. Safety and reactogenicity of various TDENV-PIV formulations from Day 0 through 28 days after the second dose (Day 0 - Day 56) [ Time Frame: Up to Day 56 ]

   Safety and Reactogenicity:

   • Occurrence, intensity and relationship to vaccination of solicited local and general adverse events (AEs) during the 7-day follow-up period post each vaccination (Day 0-6)
   • Occurrence, intensity and relationship to vaccination of unsolicited AEs during the 28-day follow-up period post each vaccination (Day 0-27)
   • Hematological and biochemical levels at study visits on Days 0, 7, 28, 35 and 56
   • Occurrence of serious adverse events (SAEs) from Day 0 to Day 56
   • Occurrence of potential immune-mediated diseases (pIMDs) and medically attended AEs from Day 0 to Day 56
2. Humoral immunogenicity to each of four DENV types of various TDENV-PIV formulations 28 days after the second dose (Day 56) [ Time Frame: Day 56 ]

   Humoral Immunogenicity:

   Neutralizing antibody titers specific to each DENV type at Day 56

   • Geometric mean titers (GMTs) of neutralizing antibody titers to each DENV type
   • Rate of fold increases in neutralizing antibody from Day 0 for each DENV type
   • Seropositivity rates for each DENV type
   • Trivalent and tetravalent seropositivity rates

Secondary Outcome Measures :

1. Safety of various TDENV-PIV formulations, from Day 0 to Month 13 (Visits 1-11) [ Time Frame: Up to month 13 ]

   Safety:

   • Hematological and biochemical levels at study visits on Months 4, 7, 10 and Month 13
   • Occurrence of pIMDs and medically attended AEs from Day 0 to Month 13
   • Occurrence of any SAE from Day 0 to Month 13
2. Humoral immunogenicity to each of four DENV types of various TDENV-PIV formulations on Days 0, 7 and 28 and Months 7 and 13 [ Time Frame: Up to month 13 ]

   Humoral Immunogenicity:

   • Geometric mean titers (GMTs) of neutralizing antibody titers to each DENV type
   • Rate of fold increases in neutralizing antibody from Day 0 for each DENV type
   • Seropositivity rates for each DENV type
   • Trivalent and tetravalent seropositivity rates
3. • To evaluate the safety of various TDENV-PIV formulations from Month 14 through the end of the study (Visit 15) [ Time Frame: Up to the end of study (Month 37-39) ]
   Occurrence of serious adverse events (SAEs) related to study procedures from Month 14 to end of study (Month 37-39)

Eligibility Criteria

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Ages Eligible for Study:	20 Years to 39 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

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 20 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
• Subject has lived in the Caribbean for more than 10 years
• 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).

• 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 Exclusion:
• 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)
• Previous or planned administration of any other flavivirus vaccine (approved or investigational) for the entire study duration
• Previous receipt of any investigational dengue virus vaccine
• 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 normal limits for their age, gender, and locality at screening.

Contacts and Locations

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Locations

Puerto Rico
Clinical Research Center, 1st Floor University Hospital
San Juan, Puerto Rico, 00936-5067

Sponsors and Collaborators

U.S. Army Medical Research and Materiel Command

GlaxoSmithKline

Walter Reed Army Institute of Research (WRAIR)

Investigators

Principal Investigator:	Clemente Diaz, MD	University of Puerto Rico

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Diaz C, Lin L, Martinez LJ, Eckels KH, Campos M, Jarman RG, De La Barrera R, Lepine E, Toussaint JF, Febo I, Innis BL, Thomas SJ, Schmidt AC. Phase I Randomized Study of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults from Puerto Rico. Am J Trop Med Hyg. 2018 May;98(5):1435-1443. doi: 10.4269/ajtmh.17-0627. Epub 2018 Mar 1.

Responsible Party:	U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier:	NCT01702857 History of Changes
Other Study ID Numbers:	S-12-12; 116614 ( Other Identifier: GSK ); WRAIR 1945 ( Other Identifier: WRAIR ); DPIV-002 ( Other Identifier: GSK Protocol # )
First Posted:	October 10, 2012
Last Update Posted:	May 23, 2017
Last Verified:	May 2017

Keywords provided by U.S. Army Medical Research and Materiel Command:

Dengue; Dengue fever; Dengue Hemorrhagic Fever; Flavivirus

Additional relevant MeSH terms:

Dengue; Arbovirus Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Hemorrhagic Fevers, Viral; Vaccines	Aluminum sulfate; Aluminum Hydroxide; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic; Antacids; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents