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Phase II Trial to Evaluate Safety and Immunogenicity of a Dengue 1,2,3,4 (Attenuated) Vaccine

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ClinicalTrials.gov Identifier: NCT01696422
Recruitment Status : Unknown
Verified January 2019 by Butantan Institute.
Recruitment status was:  Active, not recruiting
First Posted : October 1, 2012
Last Update Posted : January 16, 2019
Sponsor:
Collaborators:
Banco Nacional de Desenvolvimento Economico e Social
Fundação de Amparo à Pesquisa do Estado de São Paulo
Butantan Foundation
Information provided by (Responsible Party):
Butantan Institute

Tracking Information
First Submitted Date  ICMJE September 27, 2012
First Posted Date  ICMJE October 1, 2012
Last Update Posted Date January 16, 2019
Study Start Date  ICMJE October 2013
Actual Primary Completion Date April 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 26, 2013)
  • Safety [ Time Frame: Up to day 21 after vaccination ]
    Frequency of solicited and unsolicited local and systemic adverse reactions up to Day 21 after vaccination.
  • Immunogenicity [ Time Frame: Up to day 91 after vaccination ]
    Seroconversion rate for each of the four vaccine viruses defined by PRNT50 ≥1:10 for each vaccine virus serotype on Days 28, 56 or 91.
Original Primary Outcome Measures  ICMJE
 (submitted: September 27, 2012)
  • Safety [ Time Frame: Up to day 21 after vaccination ]
    Frequency of solicited and unsolicited local and systemic adverse reactions up to Day 21 after vaccination.
  • Immunogenicity [ Time Frame: Up to day 56 after vaccination ]
    Seroconversion rate for each of the four vaccine viruses defined by PRNT50 ≥1:10 for each vaccine virus serotype on Days 28 or 56.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2013)
  • Safety [ Time Frame: up to Day 182 after the first vaccination ]
    1. Unsolicited adverse events after Day 21 and up to Day 182 after the first vaccination;
    2. Viremia for each of the four vaccine virus on Days 3, 6, 9, 12, 15 and 21 after the first vaccination of all volunteers in Step A of study and 40 volunteers with previous exposure to Dengue of Step B. For other volunteers from Step B, viremia only is measured on Day 12.
    3. Cases of suspected and confirmed dengue in five years after the first vaccination;
  • Immunogenicity [ Time Frame: Annualy up to five years ]
    1. Response rates of monovalent, bivalent, trivalent or tetravalent, at Day 28, 56 and 91 and annually after vaccination, as measured by PRNT50 for each one of the four vaccine viruses;
    2. The difference between the geometric means, pre and post vaccination, serum level of neutralizing antibodies measured by PRNT50 for each of the four vaccine viruses evaluated until five years after the first vaccination.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 27, 2012)
  • Safety [ Time Frame: up to Day 182 after the first vaccination ]
    1. Unsolicited adverse events after Day 21 and up to Day 182 after the first vaccination;
    2. Viremia for each of the four vaccine virus on Days 3, 6, 9, 12, 15 and 21 after the first vaccination of all volunteers in Step A of study and 40 volunteers with previous exposure to Dengue of Step B. For other volunteers from Step B, viremia only is measured on Day 12.
    3. Cases of suspected and confirmed dengue in five years after the first vaccination;
  • Immunogenicity [ Time Frame: Annualy up to five years ]
    1. Response rates of monovalent, bivalent, trivalent or tetravalent, at Day 28 and 56 and annually after vaccination, as measured by PRNT50 for each one of the four vaccine viruses;
    2. The difference between the geometric means, pre and post vaccination, serum level of neutralizing antibodies measured by PRNT50 for each of the four vaccine viruses evaluated until five years after the first vaccination.
Current Other Pre-specified Outcome Measures
 (submitted: September 27, 2012)
Exploratory [ Time Frame: Up to Day 182 after the second vaccination ]
  1. The seroconversion rate for each one of the four vaccine according to previous exposure to other flaviviruses;
  2. The solicited and unsolicited local and systemic adverse reactions, until Day 21 after the second vaccination;
  3. Unsolicited adverse events after Day 21 and Day 182 after the second vaccination for participants from Step A;
  4. The differences in pre and post vaccination cellular immune response after the first and second vaccination and annually for five years for participants in Step A;
  5. Viremia for each one of the four vaccine viruses on Days 3, 6, 9, 12, 15 and 21 after a second vaccination for participants in Step A;
  6. The difference in rates of seroconversion for each of the four types vaccination after the second vaccination for participants in Step A;
  7. The differences in cellular immune response pre and post vaccination after the first vaccination and annually for five years for 40 participants from Step B with previous exposure to dengue.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Phase II Trial to Evaluate Safety and Immunogenicity of a Dengue 1,2,3,4 (Attenuated) Vaccine
Official Title  ICMJE Phase II, Step-wise, Randomized, Double-blind, Controlled Clinical Trial for Safety and Immunogenicity Evaluation of a Lyophilized Formulation of Dengue 1,2,3,4 (Attenuated) Vaccine in Healthy Adults
Brief Summary This is a phase II step-wise, randomized, multicenter, double-blind and controlled clinical trial to evaluate the safety and immunogenicity of a attenuated tetravalent lyophilized dengue vaccine manufactured by Butantan Institute. Three Clinical Sites at University of Sao Paulo - Brazil will participate in the study. A total of 300 volunteers will be recruited and divided into two steps: Step A (with no previous exposure to dengue) and Step B (with and without previous exposure to dengue). In step A the participants will be assigned to receive either the lyophilized vaccine, or the liquid vaccine(developed at NIH and produced and formulated at Butantan according to the NIH-Protocol), or the placebo. In Step B participants will be assigned to receive either the lyophilized vaccine, or the placebo. Both vaccine formulations (lyophilized and liquid) are composed of the same attenuated viruses: rDEN1∆30, rDEN2/4∆30(ME), rDEN3∆30/31, and rDEN4∆30. At the end of the study, 20 volunteers will have received the liquid formulation (NIH), 210 the lyophilized formulation (Butantan), and 70 will have received the placebo. All participants included in both steps will be followed by a period of five years after their inclusion in the study. The study hypothesis is that the investigational lyophilized dengue vaccine manufactured by Butantan Institute is safe and confers balanced immune response, after one dose of 1000PFU, to all for vaccine viruses.
Detailed Description This is a phase II step-wise, randomized, multicenter, double-blind and controlled clinical trial to evaluate the safety and immunogenicity of an attenuated tetravalent lyophilized dengue vaccine manufactured by Butantan Institute. A total of 300 volunteers will be recruited including men and no pregnant/breastfeeding women between 18 and 59 years of age complete, with and without previous exposure to dengue that will be randomized into Step A and Step B. Step A will include 50 volunteers with no previous exposure and they will be randomly assigned to receive one dose of either the lyophilized formulation (Butantan), or the liquid formulation (TetraVax-DV Vaccine - Admixture TV003 developed by NIH/NIAID and produced and formulated at Butantan according the NIH-Protocol), or the placebo. A second dose will be administered six months after the first vaccination as part of an exploratory assessment. Step B will include 250 participants(50 without previous exposure to dengue,and 200 with previous exposure to dengue) who will be randomly assigned to receive one dose of either the lyophilized formulation (Butantan),or the placebo. All participants included in both steps will be followed by a period of five years after their inclusion in the study. The vaccines will be administered at dose of 1000 PFU (for each of the vaccine viruses),and both vaccines and the placebo will be administered subcutaneously.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Dengue
Intervention  ICMJE
  • Biological: Dengue 1,2,3,4 (attenuated) vaccine
    Dose 1000 PFU per virus (1,2,3,4) Route:subcutaneous
    Other Names:
    • Butantan DV
    • Dengue Tetravalent Vaccine - Lyophilized formulation
  • Biological: TetraVax-DV Vaccine - Admixture TV003
    Dose 1000 PFU per virus (1,2,3,4) Route: subcutaneous
    Other Name: Dengue Tetravalent Vaccine - Liquid formulation
  • Other: Placebo
    Route:subcutaneous
Study Arms  ICMJE
  • Experimental: Step A: dengue lyophilized vaccine
    Dengue 1,2,3,4 (attenuated) vaccine Two doses with a six-months interval, SC
    Intervention: Biological: Dengue 1,2,3,4 (attenuated) vaccine
  • Active Comparator: Step A:dengue liquid vaccine
    TetraVax-DV Vaccine - Admixture TV003 Two doses with a six-months interval, SC
    Intervention: Biological: TetraVax-DV Vaccine - Admixture TV003
  • Placebo Comparator: Step A: Placebo
    Placebo comparator Two doses with a six-months interval, SC
    Intervention: Other: Placebo
  • Experimental: Step B: dengue lyophilized vaccine
    Dengue 1,2,3,4 (attenuated) vaccine Single dose, SC
    Intervention: Biological: Dengue 1,2,3,4 (attenuated) vaccine
  • Placebo Comparator: Step B: Placebo
    Placebo comparator Single dose, SC
    Intervention: Other: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Actual Enrollment  ICMJE
 (submitted: September 27, 2012)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Actual Primary Completion Date April 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Healthy adults (men and non-pregnant women), from 18 to 59 years old;
  • Willingness to participate throughout the study period (approximately five years);
  • Willingness to participate documented by the signature of ICF;
  • Females with childbearing potential must be willing to avoid pregnancies up to three weeks after the last vaccine dose. All female volunteers will be considered with childbearing potential unless they have documented history of hysterectomy, tubal ligation or are postmenopausal (12 months of amenorrhea after the last menstrual period).

Exclusion Criteria:

  • Pregnancy (confirmed by positive beta-hCG test) or breastfeeding;
  • Evidence of active neurological, cardiac, pulmonary, hepatic or renal disease as clinical history, physical examination and/or laboratory results;
  • Compromised immune system diseases including: diabetes mellitus, cancer (except basal cell carcinoma) and autoimmune diseases;
  • Behavioral, cognitive or psychiatric disease that in the opinion of the principal investigator or his representative physician, affects the participant ability to understand and cooperate with all study protocol requirements;
  • Values of absolute neutrophil, alanine aminotransferase (ALT) or serum creatinine count greater than or equal to Grade 1, as defined in the protocol;
  • Abusive usage of alcohol or drugs in the past 12 months that has caused medical, professional or family problems, indicated by clinical history;
  • History of severe allergic reactions or anaphylaxis;
  • Diagnosis of asthma with a history of hospitalization in the last six months due to illness;
  • Fever or suspect fever within 72 hours prior to vaccination or axillary temperature greater than 37,8°C on the day of vaccination;
  • Positive result of HIV-1 serology by screening or confirmed tests;
  • Screening or confirmed positive test for hepatitis C virus (HCV);
  • Positive test of hepatitis B virus antigen surface (AgHBs) alone or against hepatitis B "core" antigen antibody (anti-HBc);
  • Use of corticosteroids (except topical or nasal) or other immunosuppressive drugs within 42 days before study initiation/baseline. It will be considered immunosuppressive dose of corticosteroids the equivalent to a dose ≥10 mg of prednisone per day for over 14 days;
  • Use of anticoagulant medication;
  • Have received live virus vaccine within 28 days or killed virus vaccine in the last 14 days prior to vaccination, or have a scheduled immunization during the first 42 days after receiving the investigational product;
  • History of asplenia;
  • Have received blood products in the past six months, including transfusions or immunoglobulin, or scheduled administration of blood products or immunoglobulin for the first 42 days after vaccination;
  • Use of any investigational product within 42 days before or after receiving this study vaccination;
  • Has participated in another clinical trial six months prior to vaccination;
  • Denies permission for biological material storage for future research as defined in ICF;
  • Any other condition that might put in risk the safety/rights of a potential participant or hurdle his/her compliance with this protocol in investigator's opinion or his representative physician.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 59 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01696422
Other Study ID Numbers  ICMJE DEN-01-IB
U1111-1135-4553 ( Registry Identifier: UTN )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Butantan Institute
Study Sponsor  ICMJE Butantan Institute
Collaborators  ICMJE
  • Banco Nacional de Desenvolvimento Economico e Social
  • Fundação de Amparo à Pesquisa do Estado de São Paulo
  • Butantan Foundation
Investigators  ICMJE
Study Director: Alexander R Precioso, MD, PhD Instituto Butantan
PRS Account Butantan Institute
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP