Clinical trial NCT00842530: Efficacy and Safety of Dengue Vaccine in Healthy Children
Official title: Efficacy and Safety of Dengue Vaccine in Healthy Children Aged 4 to 11 Years in Thailand
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Dengue Virus
Dengue Fever
Dengue Hemorrhagic Fever
Dengue Diseases
Keywords: Dengue virus
Dengue fever
Dengue hemorrhagic fever
Dengue diseases
Dengue vaccine
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2009-02-12
Enrollment: 4002
Sex: ALL
Minimum age (years): 4
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The primary objective of the study was to assess the efficacy of CYD dengue vaccine after three injections in preventing symptomatic virologically-confirmed dengue (VCD) cases, regardless of the severity, due to any of the four serotypes in children aged 4 to 11 years at the time of inclusion.

Secondary objectives included to assess:

* Vaccine efficacy against severe VCD cases
* Vaccine efficacy against VCD cases following at least two injections with CYD dengue vaccine
* Immune response to CYD dengue vaccine
* Safety profile of CYD dengue vaccine. Safety assessments include solicited reactions within 7 or 14 days after each injection, unsolicited adverse events within 28 days after each injection, and serious adverse events during the study period.

Other objectives included:

* Vaccine efficacy against VCD cases following at least one injection with CYD dengue vaccine
* Vaccine efficacy against VCD cases due to each serotype
* Participants with clinical signs and symptoms for VCD

Detailed description: Participants (both cohort 1 and 2) received 3 injections of CYD dengue vaccine. Participants (Cohort 1) received rabies vaccine at Month 0 and placebo at 6 and 12 months. Participants (cohort 2) received placebo at 0, 6, and 12 months.

Dengue cases were collected for assessment of efficacy during the Active Phase from first injection until at least 13 months after the third injection. A subset of participants were also evaluated for reactogenicity and immunogenicity.

Symptomatic VCD cases were defined as acute febrile illness with fever lasting for at least 1 day (temperature \>= 37.5°C measured at least twice with an interval of at least 4 hours), confirmed by reverse transcriptase-polymerase chain reaction and/or dengue non-structural protein 1 (NS1) enzyme-linked immunosorbent assay antigen test, and occurring \>28 days after the third injection.

Dengue hemorrhagic fever (DHF) Grade I, II, III, and IV according to the 1999 World Health Organization (WHO) definition:

Clinical Manifestations: a) Fever: acute onset, high and continuous, lasting 2 to 7 days. b) Any of the following hemorrhagic manifestations (including at least a positive tourniquet test): petechiae, purpura, ecchymosis, epistaxis, gum bleeding, and hematemesis and/or melena.

Laboratory Findings: c) thrombocytopenia (platelet count = 100 000/mm3 or less) d) Plasma leakage as shown by hemoconcentration (hematocrit increased by 20% or more) or pleural effusion (seen on chest X-ray) and/or hypoalbuminemia.

DHF was graded as follows: Grade I: Fever accompanied by non-specific constitutional symptoms; the only hemorrhagic manifestation is a positive tourniquet test. Grade II: Spontaneous bleeding in addition to the manifestations of Grade I participants, usually in the form of skin and/or other hemorrhages. Grade III: Circulatory failure manifested by rapid and weak pulse, narrowing of pulse pressure (20 mmHg or less) or hypotension, with the presence of cold clammy skin and restlessness. Grade IV: Profound shock with undetectable blood pressure and pulse.

Independent Data Monitoring Committee (IDMC) severity criteria:- 1) Thrombocytopenia: platelet count ≤ 50 000/mm\^3 ; 2) Any hemorrhage that needs blood transfusion; 3) Objective evidence of capillary permeability documented by one or several of the following: a) Increase in hematocrit by \>= 20 percent (%) compared to normal for age, or \[(Maximum hematocrit - minimum hematocrit)/min\]\*100% \>= 20%, b) Pleural or abdominal (ascites) effusion (diagnosed either by clinical signs or radiography or other imaging method), c) Hypoproteinemia; 4) Signs of circulatory failure manifested by: a) Narrow pulse pressure \<20mm Hg, or hypotension for age (as defined by systolic pressure \<80 mm Hg in children \<5 years and systolic pressure \< 90 mm Hg in children \>= 5 years), and b) Rapid and weak pulse, and c) Signs of poor capillary perfusion (cold and clammy extremities, delayed capillary refill); 5) Visceral Manifestations such as: a) Neurological symptoms (convulsions or change in level of consciousness), b) Hepatic failure or elevation of hepatic enzyme (\>5-fold normal level), c) Metabolic (hypoglycemia) or electrolyte (hyponatremia, hypocalcemia) disturbances or volume overload (acute pulmonary edema or congestive heart failure), d) Other visceral manifestations such as cardiomyopathy, acute renal failure, acute respiratory failure, cholecystitis.

Eligibility criteria: Inclusion Criteria :

* Aged 4 to 11 years on the day of inclusion.
* Participant in good health, based on medical history and physical examination.
* Provision of assent form signed by the participants (for participants \>= 7 years old) and informed consent form signed by the parent or another legally acceptable representative.
* Participant and parent/ legally acceptable representative able to attend all scheduled visits and to comply with all trial procedures.
* Participant attended one of the schools involved in the trial and living in the Ratchaburi Province.
* For a female participant of child-bearing potential (girls post-menarche), avoid becoming pregnant (use of an effective method of contraception or abstinence) for at least 4 weeks prior to first vaccination, until at least 4 weeks after the last vaccination.

Exclusion Criteria :

* Febrile illness (temperature \>= 37.5°C) or moderate or severe acute illness/infection on the day of vaccination, according to Investigator judgment.
* For a female participant of child-bearing potential (girls post-menarche), known pregnancy or positive urine pregnancy test on the day of the first trial vaccination.
* Personal or family history of thymic pathology (thymoma), thymectomy, or myasthenia.
* Planned participation in another clinical trial during the present trial period.
* Known or suspected congenital or acquired immunodeficiency, immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy, or long-term systemic corticosteroids therapy.
* Known systemic hypersensitivity to any of the vaccine components or history of a life-threatening reaction to the trial vaccines or to a vaccine containing any of the same substances.
* Chronic illness at a stage that could interfere with trial conduct or completion, in the opinion of the Investigator.
* Receipt of blood or blood-derived products in the past 3 months.
* Participant deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized without his/her consent.
* Participation in another clinical trial investigating a vaccine, drug, medical device, or a medical procedure in the 4 weeks preceding the first trial vaccination.
* Receipt of any vaccine in the 4 weeks preceding the first trial vaccination.
* Planned receipt of any vaccine in the 4 weeks following the first trial vaccination.e
* Participant who plans to attend another school (outside the trial area) or move to another city in the coming 30 months.

Primary outcomes:
measure: Number of Symptomatic Virologically-Confirmed Dengue (VCD) Cases During the Active Phase Post-dose 3 Following Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: 28 days Post-Inj. 3 up to the end of Active Phase (up to 13 months Post-Inj. 3, i.e. up to 25 months)
Secondary outcomes:
measure: Number of Severe VCD Cases During the Active Phase Post-dose 3 Following Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: 28 days Post-Inj. 3 up to the end of Active Phase (up to 13 months Post-Inj. 3, i.e. up to 25 months)
measure: Number of Symptomatic VCD Cases During the Active Phase Following at Least Two Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: 28 days Post-Inj. 2 up to Inj. 3, 28 days Post-Inj. 2 up to end of Active Phase ( up to 25 months)
measure: Geometric Mean Titers (GMTs) of Antibodies Against Each Serotype With the Parental Dengue Virus Strain Before and Following Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: Pre-Inj. 1, 2, and 3, 28 days Post-Inj. 1, 2 and 3 and 1 year Post-Inj. 3
measure: GMTs of Antibodies Against Each Serotype With the Parental Dengue Virus Strain in Dengue-Immune Participants Before and Following Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: Pre-Inj. 1, 2, and 3, 28 days Post-Inj. 1, 2 and 3 and 1 year Post-Inj. 3
measure: GMTs of Antibodies Against Each Serotype With the Parental Dengue Virus Strain in Dengue Non-Immune Participants Before and Following Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: Pre-Inj. 1, 2, and 3, 28 days Post-Inj. 1, 2 and 3 and 1 year Post-Inj. 3
measure: Percentage of Participants With Solicited Inj. Site Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: 7 days post-any Inj. and each of the 3 Inj.
measure: Percentage of Participants With Solicited Systemic Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: 14 days post-any Inj. and each of the 3 Inj.
Other outcomes:
measure: Number of Symptomatic VCD Cases During the Active Phase Following at Least One Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: Day 0 (Post-Inj.) up to end of Active phase (up to 25 months); 28 days post-Inj. 1 up to end of Active phase (up to 25 months)
measure: Number of Participants With One VCD Episode During the Active Phase Due to Each Serotypes Following Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: After 28 days Post Inj. 3 up to the end of Active Phase (up to 25 months)
measure: Mean Number of Days for Clinical Signs and Symptoms (Fever, Clinical Syndrome and Hospitalization) of VCD During the Active Phase Following Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: Day 0 (Post-Inj.) up to end of Active Phase (up to 25 months)
measure: Number of Participants Requiring Hospitalization for VCD During the Active Phase Following Inj. With Either CYD Dengue Vaccine or a Placebo
timeFrame: Day 0 (Post-Inj.) up to end of Active Phase (up to 25 months)
Locations:
city: Bangkok
country: Thailand
facility: Sanofi Pasteur Investigational Site
Study officials:
affiliation: Sanofi Pasteur, a Sanofi Company
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
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