Immunogenicity and Safety of a Tetravalent Dengue Vaccine Booster Injection in Subjects Who Previously Completed a 3-dose Schedule

• ClinicalTrials.gov Identifier: NCT02824198
• Recruitment Status: Completed
• First Posted: July 6, 2016
• Results First Posted: June 14, 2019
• Last Update Posted: December 16, 2019
• Sponsor: Sanofi Pasteur, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Sanofi Pasteur, a Sanofi Company )

Tracking Information

• First Submitted Date: July 1, 2016
• First Posted Date: July 6, 2016
• Results First Submitted Date: May 24, 2019
• Results First Posted Date: June 14, 2019
• Last Update Posted Date: December 16, 2019
• Actual Study Start Date: July 1, 2016
• Actual Primary Completion Date: March 18, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 24, 2019)

Geometric Mean Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype Following Booster Injection With CYD Dengue Vaccine in CYD63 Compared to the Third CYD Dengue Vaccine Injection Received in Study CYD28: CYD Dengue Vaccine Booster Group [ Time Frame: 28 days post-dose 3 in CYD28 and 28 days post-booster injection in CYD63 ]

GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) were assessed using the plaque reduction neutralization test (PRNT).

Original Primary Outcome Measures (submitted: July 5, 2016)

Neutralizing antibody levels against each dengue virus serotype measured 28 days after the third CYD dengue vaccine injection and 28 days after the booster injection in the CYD Dengue Vaccine Group [ Time Frame: Day 0 (pre-vaccination) and Day 28 post-booster vaccination ]

Neutralizing antibody levels against each dengue virus serotype will be measured using dengue plaque reduction neutralization test (PRNT).

Current Secondary Outcome Measures (submitted: December 6, 2019)

• GMTs of Antibodies Against Each Dengue Virus Serotype Before and Following Booster Injection (Inj.) With Either CYD Dengue Vaccine or Placebo [ Time Frame: Pre-booster injection (Day 0) and 28 days post-booster injection ]
  GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT.
• GMTRs of Antibodies Against Each Dengue Virus Serotype Before and Following Booster Injection With Either CYD Dengue Vaccine or Placebo [ Time Frame: Pre-booster injection (Day 0) and 28 days post-booster injection ]
  GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT. GMTRs were calculated as the ratio of GMTs post-booster injection and pre-booster injection.
• Percentage of Participants With Seropositivity Against Each Dengue Virus Serotype Before and Following Booster Injection With Either CYD Dengue Vaccine or Placebo [ Time Frame: Pre-booster injection (Day 0) and 28 days post-booster injection ]
  Seropositivity against each dengue virus serotype were measured using dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titers >=10 (1/dilution).
• Percentage of Participants With Seroconversion Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo [ Time Frame: 28 days post-booster injection ]
  Seroconversion rates for each serotypes were defined as the percentages of participants with either a pre-booster titer < 10 (1/dilution) and a post-booster titer >= 40 (1/dilution), or a pre-booster titer >=10 (1/dilution) and a >= 4-fold increase in post-booster titer as determined by PRNT.
• GMTs of Antibodies Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received In Study CYD28 and Before Booster Injection With Either CYD Dengue Vaccine or Placebo in CYD63 [ Time Frame: 28 days post-dose 3 in CYD28 and pre-booster injection (Day 0) in CYD 63 ]
  GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) were assessed using the PRNT.
• GMTRs of Antibodies Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received in Study CYD28 And Before Booster Injection With Either CYD Dengue Vaccine or Placebo [ Time Frame: 28 days post-dose 3 in CYD28 and pre-booster injection (Day 0) in CYD63 ]
  GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) were assessed using the PRNT. GMTRs were calculated as the ratio of GMTs post-dose 3 in CYD28 and pre-booster injection in CYD63.
• Percentage of Participants With Seropositivity Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received in Study CYD28, and Following Booster Injection With Either CYD Dengue Vaccine or Placebo [ Time Frame: 28 days post-dose 3 in CYD28 and 28 days post-booster injection in CYD63 ]
  Seropositivity against each dengue virus serotype were measured using dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titers >=10 (1/dilution).
• GMTs of Antibodies Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo [ Time Frame: 6 months, 12 months, and 24 months post-booster injection ]
  GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT.
• GMTRs of Antibodies Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo [ Time Frame: Pre-booster injection (Day 0) and 6 months, 12 months, 24 months post-booster injection ]
  GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT. GMTRs were calculated as the ratio of GMTs post-booster injection and pre-booster injection.
• Percentage of Participants With Seropositivity Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo [ Time Frame: 6 months, 12 months, and 24 months post-booster injection ]
  Seropositivity against each dengue virus serotype were measured using dengue PRNT. Seropositive participants were defined as the participants with neutralizing antibody titers >=10 (1/dilution).
• Number of Participants Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Booster Injection With Either CYD Dengue Vaccine or Placebo [ Time Frame: Within 7 days after booster injection ]
  Solicited injection site reactions: Pain, Erythema, and Swelling. Grade 3 injection site reactions: Pain: significant; prevents daily activity; Erythema and Swelling: >100 millimeter.
• Number of Participants Reporting Solicited Systemic Reactions (Fever, Headache, Malaise, Myalgia, Asthenia) Following Booster Injection With Either CYD Dengue Vaccine or Placebo [ Time Frame: Within 14 days after booster injection ]
  Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 reactions: Fever: >=39 degree Celsius; Headache, Malaise, Myalgia, and Asthenia: significant, prevents daily activity.

Original Secondary Outcome Measures (submitted: July 5, 2016)

• Neutralizing antibody levels against each of the four parental dengue virus strains of the CYD dengue vaccine as determined by PRNT immediately prior and 28 days post booster or placebo injection [ Time Frame: Day 0 (pre-vaccination) and Day 28 post-booster vaccination ]
  Neutralizing antibody levels against each dengue virus serotype will be measured using dengue plaque reduction neutralization test (PRNT).
• Number of subjects with seroconversion 28 days after injection for each of the 4 parental dengue virus strains of CYD dengue vaccine [ Time Frame: Day 0 (pre-vaccination) and 28 days post-booster injection ]
  Neutralizing antibody levels against each dengue virus serotype will be measured using dengue plaque reduction neutralization test (PRNT). Seroconversion is percentage of subjects with either a pre-booster titer < 10 (1/dil) and a post-booster titer ≥ 40 (1/dil), or a pre-booster titer ≥ 10 (1/dil) and a ≥ 4-fold increase in post-booster titer
• Summary of neutralizing antibody levels against each of the four parental dengue virus strains after the third CYD dengue vaccine injection and immediately prior to booster or placebo injection [ Time Frame: Day 0 (pre-vaccination) and Day 28 post-booster vaccination ]
  Neutralizing antibody levels against each dengue virus serotype will be measured using dengue plaque reduction neutralization test (PRNT).
• Summary of neutralizing antibody levels against each of the four parental dengue virus strains at 6 months, 1 year and 2 years post booster or placebo injection [ Time Frame: 6 Months up to 2 years post-booster vaccination ]
  Neutralizing antibody levels against each dengue virus serotype will be measured using dengue plaque reduction neutralization test (PRNT).
• Number of participants reporting solicited injection site reactions, solicited systemic reactions, unsolicited adverse events, and serious adverse events occurring during trial [ Time Frame: Day 0 up to 2 years post-vaccination ]
  Solicited injection-site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever (temperature), Headache, Malaise, Myalgia, and Asthenia

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Immunogenicity and Safety of a Tetravalent Dengue Vaccine Booster Injection in Subjects Who Previously Completed a 3-dose Schedule
• Official Title: Immunogenicity and Safety of a Tetravalent Dengue Vaccine Given as a Booster Injection in Adolescents and Adults Who Previously Completed the 3-dose Schedule in a Study Conducted in Singapore

Brief Summary

The aim of the study was to assess and describe the booster effect of a tetravalent CYD dengue vaccine dose administered about 5 years or more after the completion of a 3-dose vaccination schedule in Singapore.

Primary Objective:

• To demonstrate the non-inferiority in terms of geometric mean of titer ratios (GMTRs) of a CYD dengue vaccine booster compared to the third CYD dengue vaccine injection in participants from CYD28 trial (participants from Group 1 only).

Secondary Objectives:

• If the primary objective of non-inferiority achieved: To demonstrate the superiority, in terms of GMTRs, of a CYD dengue vaccine booster compared to the third CYD dengue vaccine injection in participants from CYD28 trial (participants from Group 1 only).
• To describe the immune responses elicited by the CYD dengue vaccine booster or placebo injection in participants who received three doses of the CYD dengue vaccine in the CYD28 trial in all participants.
• To describe the neutralizing antibody levels of each dengue serotype Post Dose 3 (CYD28 participants) and immediately prior to booster or placebo injection in all participants.
• To describe the neutralizing antibody persistence 6 months, 1 year and 2 years post booster or placebo injection in all study participants.
• To evaluate the safety of booster vaccination with CYD dengue vaccine in all participants.

• Detailed Description: Healthy adolescents and adults received 3 doses of the tetravalent dengue vaccine 5-6 years earlier in a previous CYD dengue vaccine trial (CYD28 - NCT00880893) received either a booster injection of CYD dengue vaccine or a placebo on Day 0. They were evaluated for safety and antibody persistence of the booster injection up to 2 years post-vaccination.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:

An observer-blind procedure was followed for the injection of CYD dengue vaccine or placebo. Neither the blind-observer Investigator nor the participants (and/or participants' parent(s)/legally acceptable representative(s) for participants aged < 21 years) knew which product was administered.

Primary Purpose: Prevention

Condition

• Dengue Fever
• Dengue Hemorrhagic Fever

Intervention

• Biological: CYD Dengue Vaccine (5 dose formulation)
  0.5 mL, Subcutaneous
• Biological: Placebo, NaCl 0.9%
  0.5 mL, Subcutaneous

Study Arms

• Experimental: CYD Dengue Vaccine booster Group
  Participants who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received a booster injection of CYD dengue vaccine at Day 0 in this study (CYD63).
  Intervention: Biological: CYD Dengue Vaccine (5 dose formulation)
• Placebo Comparator: Placebo Group
  Participants who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received an injection of a placebo at Day 0 in this study (CYD63).
  Intervention: Biological: Placebo, NaCl 0.9%

• Publications *: Park J, Archuleta S, Oh MH, Shek LP, Jin J, Bonaparte M, Fargo C, Bouckenooghe A. Immunogenicity and safety of a dengue vaccine given as a booster in Singapore: a randomized Phase II, placebo-controlled trial evaluating its effects 5-6 years after completion of the primary series. Hum Vaccin Immunother. 2020 Mar 3;16(3):523-529. doi: 10.1080/21645515.2019.1661204. Epub 2019 Nov 5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 24, 2019): 118
• Original Estimated Enrollment (submitted: July 5, 2016): 260
• Actual Study Completion Date: January 18, 2019
• Actual Primary Completion Date: March 18, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Had been identified as a potential participant by the Sponsor, and was included in the list provided to the investigator (i.e., aged 9 to 45 years on the day of first injection of CYD dengue vaccine in CYD28, had received 3 doses of CYD dengue vaccine in the CYD28 trial, and had a post-dose 3 serum sample available).
• Participants with good health, based on medical history and physical examination.
• Informed consent form (ICF) had been signed and dated by participant (based on local regulations), and ICF had been signed and dated by the parent(s) or another legally acceptable representative (and by an independent witness if required by local regulations).
• Participant and parent(s)/legally acceptable representative(s) was able to attend all scheduled visits to comply with all trial procedures.

Exclusion Criteria:

• Participant who received any other dengue vaccination that was not part of CYD28.
• Participant was pregnant, or lactating, or of childbearing potential (considered of non childbearing potential, a female must be pre-menarche or post-menopausal for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to vaccination until at least 4 weeks after vaccination).
• Participation at the time of study enrollment (or in the 4 weeks preceding the trial vaccination) or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure.
• Receipt of any vaccine in the 4 weeks preceding the trial vaccination or planned receipt of any vaccine in the 4 weeks following the trial vaccination
• Receipt of immune globulins, blood or blood-derived products in the past 3 months.
• Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months).
• Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccines used in the trial or to a vaccine containing any of the same substances.
• Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere with trial conduct or completion.
• Receipt of blood or blood-derived products in the past 3 months, which might interfere with assessment of the immune response.
• Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
• Current alcohol abuse or drug addiction.
• Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature >= 38.0°C). A prospective participant should not be included in the study until the condition had resolved or the febrile event had subsided.
• Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 14 Years to 50 Years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Singapore

Administrative Information

• NCT Number: NCT02824198
• Other Study ID Numbers: CYD63; U1111-1161-2813 ( Other Identifier: WHO )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/

• Responsible Party: Sanofi ( Sanofi Pasteur, a Sanofi Company )
• Study Sponsor: Sanofi Pasteur, a Sanofi Company
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Sanofi Pasteur Inc.

• PRS Account: Sanofi
• Verification Date: December 2019