Study of a Novel Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 14 Years in Asia

Phase 3

Completed

Conditions: Dengue
Dengue Fever
Dengue Hemorrhagic Fever

Interventions: Biological: Live, attenuated, dengue serotype 1, 2, 3, 4 virus

Registration Number: NCT01373281

Lead Sponsor: Sanofi Pasteur, a Sanofi Company

Brief Summary: The aim of the trial was to assess the efficacy of the CYD dengue vaccine in preventing symptomatic, virologically-confirmed dengue (VCD) cases.

Primary Objective:

To assess the efficacy of CYD dengue vaccine after 3 vaccinations at 0, 6, and 12 months in preventing symptomatic VCD cases, regardless of the severity, due to any of the four serotypes in children aged 2 to 14 years at the time of inclusion.

Secondary Objectives:

* To describe the efficacy of CYD dengue vaccine in preventing symptomatic VCD cases after the third dose to the end of the Active Phase, after at least 1 dose, and after 2 doses.

* To describe the occurrence of serious adverse events (SAEs), including SAEs of special interest in all participants throughout the trial period.

* To describe the occurrence of hospitalized virologically-confirmed dengue (VCD) cases and the occurrence of severe (clinically-severe or as per World Health Organization (WHO) criteria) VCD cases, throughout the Surveillance Expansion period (SEP) and throughout the trial (from Day 0 to the end of the study).

* To describe the antibody response to each dengue serotype after Dose 2, after Dose 3, and 1 and 5 years after Dose 3.

Detailed Description: Participants were randomized to either receive 3 injections of CYD dengue vaccine or a placebo at 0, 6, and 12 months.

A subset of participants from each country were also evaluated for reactogenicity and immunogenicity.

Participants who consented to participate in the SEP were actively followed for dengue case detection (i.e. at least weekly contact and capturing any acute febrile illness, not just hospitalized febrile cases, as in the Active Phase). The SEP was designed to maximize the detection of symptomatic confirmed dengue (hospitalized or not) in order to describe CYD dengue vaccine efficacy and safety in preventing symptomatic dengue. Participants who declined participating in the SEP continued surveillance as in the Hospital Phase until trial completion.

Symptomatic VCD cases occurring more than (\>) 28 days after dose 3 (during the Active Phase) are defined as:

* Acute febrile illness (i.e. temperature \>=38 C on at least 2 consecutive days)

* Virologically confirmed by dengue Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and/or dengue non-structural (NS)1 enzyme-linked immunosorbent assay (ELISA) Ag test

1997 WHO Classification Dengue hemorrhagic fever (DHF) cases were defined as per the 1997 WHO criteria of clinical manifestations; a) Fever: acute onset, high (\>= 38°C) and continuous, lasting 2 to 7 days and (b) any of the pre-listed hemorrhagic manifestations and laboratory findings of thrombocytopenia (platelet\<=100 x 109/L) and plasma leakage as shown by hemoconcentation (hematocrit increased by 20 percent \[%\] or more) or pleural effusion (seen on chest X-ray \[CXR\]) and/or ascites and/or hypoaluminemia. The first two clinical criteria plus thrombocytopenia and signs of plasma leakage are enough to establish a clinical diagnosis of DHF.

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; and Grade IV: Profound shock with undetectable blood pressure and pulse.

Independent Data Monitoring Committee (IDMC) severity criteria The severity of VCD cases was assessed by an Independent IDMC using pre-defined standardized criteria. Following manifestations of severity were considered in all suspected VCD cases; 1) Platelet count \<= 100000μl and bleeding (tourniquet, petechiae or any bleeding) plus plasma leakage (effusion on CXR OR clinically apparent ascites or hematocrit \>=20% above baseline recovery level) 2) Shock (pulse pressure \<= 20 mmHg in a child, or hypotension \[\<= 90 mmHg\] with tachycardia, weak pulse and poor perfusion) 3) Bleeding requiring blood transfusion 4) Encephalopathy i.e. Unconsciousness or poor conscious state or convulsionsfitting not attributable to simple febrile convulsion as defined in the guidelines for definition and collection of febrile convulsions or focal neurological signs. Poor conscious state or unconsciousness must be supported by Glasgow Coma Scale (GCS) score. 5) Liver impairment (aspartate aminotransferase \[AST\] \>1000IU/L or prothrombin time \[PT\] International normalized ratio \[INR\] \>1.5) excluding other causes of viral hepatitis 6) Impaired kidney function (serum creatinine ≥ 1.5 mg/dL) 7) Myocarditis, pericarditis or clinical heart failure supported by CXR, echocardiography, electrocardiogram (ECG) or cardiac enzymes.

The designation of such cases as severe or otherwise will be made on a case by case basis by the IDMC.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10275

Inclusion Criteria

Aged 2 to 14 years on the day of inclusion and resident of the site zone
Participant was in good health, based on medical history and physical examination
Assent form or informed consent form has been signed and dated by the participant (based on local regulations), and informed consent form has been signed and dated by the parent(s) or another legally acceptable representative (and by an independent witness if required by local regulations)
Participant attended all scheduled visits and to comply with all trial procedures.

Exclusion Criteria

Participant was pregnant, or lactating, or was of childbearing potential (to be considered of non-childbearing potential, a female must be pre-menarche for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination until at least 4 weeks after the last vaccination)
Participation in another clinical trial investigating a vaccine, drug, medical device, or a medical procedure in the 4 weeks preceding the first trial vaccination
Planned participation in another clinical trial during the present trial period
Self-reported 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 corticosteroids therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months)
Self-reported seropositivity for Human Immunodeficiency Virus (HIV) infection
Self-reported systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine 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
Planned receipt of any vaccine in the 4 weeks following any trial vaccination
Deprived of freedom by administrative or court order, or in an emergency setting, or hospitalized involuntarily
Current alcohol abuse or drug addiction that might interfere with the ability to comply with trial procedures
Identified as a site employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as a family member (i.e., immediate, husband, wife and their children, adopted or natural) of the site employees or the Investigator.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dengue Vaccine Group	Live, attenuated, dengue serotype 1, 2, 3, 4 virus	Participants were to receive CYD dengue vaccine at 0, 6, and 12 months.

Primary Outcome Measures

Name	Time	Method
Number of Symptomatic Virologically Confirmed Dengue (VCD) Cases Due to Any Serotype During the Active Phase Post-dose 3 Following Injection (Inj.) With Either CYD Dengue Vaccine or a Placebo	28 days and up to 13 months post-dose 3	Symptomatic VCD cases were defined as occurrence of acute febrile illness (temperature \>=38°C on at least 2 consecutive days) and confirmation of dengue virus infection by dengue reverse transcriptase polymerase chain reaction and/or dengue NS protein 1 antigen enzyme-linked immunosorbent assay. Vaccine efficacy was defined as 1 minus the ratio of density incidence due to any serotype after at least 1 dose in the CYD Dengue Vaccine Group over the density incidence of the Placebo Vaccine Group.

Secondary Outcome Measures

Name	Time	Method
Geometric Mean Titers of Antibodies Against Each Serotype With the Parental Dengue Virus Strain Before and Following Injection With Either CYD Dengue Tetravalent Vaccine or a Placebo	Pre-injection 1, 28 days post Injections 2 and 3, 13 months (Visit 07) and 60 months (Visit 12) post-injection 3	Geometric mean titers against each of the 4 serotypes of dengue virus strains were assessed using the plaque reduction neutralization test (PRNT) in a pre-defined subset of participants.
Percentage of Participants With Antibody Titers >= 10 1/Dilution (1/Dil) Against Each Dengue Virus Serotype Strain Before and Following Inj. With CYD Dengue Vaccine or Placebo	Pre-injection 1, 28 days post Injections 2 and 3, 13 months (V 07) and 60 months (V 12) post-injection 3	Percentage of participants with antibody titers \>= 10 (1/Dil) against each serotypes of the dengue virus strains were assessed using PRNT in a pre-defined subset of participants.
Number of Clinically Severe VCD Cases During the Surveillance Expansion Period Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo	From consent to participate in the Surveillance Expansion Period to 60 months post-injection 3 (up to Month 72)	The severity of VCD cases was assessed by an IDMC based on a medical review of cases and any of the following criteria:1) Platelet count \<=100000μl and bleeding (tourniquet, petechiae or any bleeding) plus plasma leakage 2) Shock (pulse pressure \<= 20mmHg in a child, or hypotension \[\<= 90 mmHg\] with tachycardia, weak pulse and poor perfusion) 3) Bleeding requiring blood transfusion 4) Encephalopathy i.e. Unconsciousness or poor conscious state or fitting not attributable to simple febrile convulsion or focal neurological signs. Poor conscious state or unconsciousness must be supported by GCS score 5) Liver impairment (AST \>1000 IU/L or PT INR \>1.5) excluding other causes of viral hepatitis 6) Impaired kidney function (serum creatinine \>= 1.5 mg/dL) 7) Myocarditis, pericarditis or clinical heart failure supported by CXR, echocardiography, ECG or cardiac enzymes.
Number of Hospitalized VCD Cases Throughout the Trial Due to Any Serotype Following Injection With Either CYD Dengue Vaccine or a Placebo	Day 0 to the end of study (up to 72 months)	Hospitalized VCD cases were defined as VCD confirmed by dengue RT-PCR and/or dengue NS1 ELISA in participants with acute febrile illness (temperature \>=38°C on at least 2 consecutive days) requiring hospitalization.
Number of Hospitalized VCD Cases During the Surveillance Expansion Period Due to Any Serotype Following Injection With Either CYD Dengue Vaccine or a Placebo	From consent to participate in the Surveillance Expansion Period to 60 months post-injection 3 (up to Month 72)	Hospitalized VCD cases were defined as VCD confirmed by dengue RT-PCR and/or dengue NS1 ELISA in participants with acute febrile illness (temperature \>= 38°C on at least 2 consecutive days) requiring hospitalization.
Number of Symptomatic VCD Cases Due to Any Serotype Occurring 28 Days Post-dose 1 Following Injection With Either CYD Dengue Vaccine or a Placebo	28 days post-injection 1 and up to 13 months post-injection 3	Symptomatic VCD cases were defined as occurrence of acute febrile illness (temperature \>= 38°C on at least 2 consecutive days) and confirmation of dengue virus infection by dengue reverse transcriptase polymerase chain reaction and/or dengue NS1 enzyme-linked immunosorbent assay. Vaccine efficacy was defined as 1 minus the ratio of density incidence due to any serotype after at least 1 dose in the CYD Dengue Vaccine Group over the density incidence of the Placebo Vaccine Group.
Number of Symptomatic VCD Cases Due to Any Serotype 28 Days Post-dose 2 Following Injection With Either CYD Dengue Vaccine or a Placebo	28 days post-injection 2 and up to 13 months post-injection 3	Symptomatic VCD cases were defined as occurrence of acute febrile illness (temperature \>= 38°C on at least 2 consecutive days) and confirmation of dengue virus infection by dengue reverse transcriptase polymerase chain reaction and/or dengue NS1 enzyme-linked immunosorbent assay. Vaccine efficacy was defined as 1 minus the ratio of density incidence due to any serotype after at least 1 dose in the CYD Dengue Vaccine Group over the density incidence of the Placebo Vaccine Group.
Number of Participants With Solicited Injection Site Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo	Within 7 days after injection	Solicited injection site reactions: Pain, Erythema, and Swelling. Grade 3 reactions (2-11 years): Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, \>= 50 mm. Grade 3 Solicited injection site reactions (12-14 years): Pain, Significant, prevents daily activity; Erythema and Swelling, \>100 mm.
Number of Symptomatic VCD Cases Due to Any Serotype During the Active Phase in Either CYD Dengue Vaccine or Placebo Group	Day 0 up to 13 months post-injection 3	Symptomatic VCD cases were defined as occurrence of acute febrile illness (temperature \>=38°C on at least 2 consecutive days) and confirmation of dengue virus infection by dengue reverse transcriptase polymerase chain reaction and/or dengue NS1 enzyme-linked immunosorbent assay. Vaccine efficacy was defined as 1 minus the ratio of density incidence due to any serotype after at least 1 dose in the CYD Dengue Vaccine Group over the density incidence of the Placebo Vaccine Group.
Number of Clinically Severe VCD Cases Throughout the Trial Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo	Day 0 to the end of study (up to 72 months)	The severity of VCD cases was assessed by an IDMC based on a medical review of cases and any of the following criteria:1) Platelet count \<=100000 μl and bleeding (tourniquet, petechiae or any bleeding) plus plasma leakage 2) Shock (pulse pressure \<= 20 mmHg in a child, or hypotension \[\<= 90 mmHg\] with tachycardia, weak pulse and poor perfusion) 3) Bleeding requiring blood transfusion 4) Encephalopathy i.e. Unconsciousness or poor conscious state or fitting not attributable to simple febrile convulsion or focal neurological signs. Poor conscious state or unconsciousness must be supported by GCS score 5) Liver impairment (AST \>1000 IU/L or PT INR \>1.5) excluding other causes of viral hepatitis 6) Impaired kidney function (serum creatinine \>= 1.5 mg/dL) 7) Myocarditis, pericarditis or clinical heart failure supported by CXR, echocardiography, ECG or cardiac enzymes.
Number of Symptomatic VCD Cases Meeting 1997 WHO Criteria Throughout the Trial Due to Any Serotype Following Injection With Either CYD Dengue Vaccine or a Placebo	Day 0 to the end of study (up to 72 months)	Dengue hemorrhagic fever cases were defined as number of participants with at least one symptomatic VCD episode meeting the 1997 WHO criteria. (a) Fever: acute onset, high (\>= 38°C) and continuous, lasting 2 to 7 days and (b) any of the pre-listed hemorrhagic manifestations and laboratory findings of thrombocytopenia (platelet \<=100 x 109/L) and plasma leakage as shown by hemoconcentation (hematocrit increased by 20% or more) or pleural effusion (seen on CXR) and/or ascites and/or hypoaluminemia. The first two clinical criteria plus thrombocytopenia and signs of plasma leakage are enough to establish a clinical diagnosis of DHF. Dengue hemorrhagic fever 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 hemorrhage.
Number of Symptomatic VCD Cases Meeting 1997 WHO Criteria During the Surveillance Expansion Period Due to Any Serotype Following Inj. With Either CYD Dengue Vaccine or a Placebo	From consent to participate int the Surveillance Expansion Period to 60 months post-injection 3 (up to Month 72)	The 1997 WHO criteria are: a) Fever: acute onset, high (\>= 38°C) and continuous, for 2 to 7 days and (b) any of the following: thrombocytopenia (platelet \<=100 x 109/L) and plasma leakage as shown by hematocrit increased by 20% or more or pleural effusion and/or ascites and/or hypoaluminemia. The first two clinical criteria plus thrombocytopenia and signs of plasma leakage are enough to establish diagnosis of DHF. Dengue hemorrhagic fever 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 participant,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; and Grade IV: Profound shock with undetectable blood pressure and pulse.
Number of Participants With Systemic Reactions Following Any and Each Inj. With Either CYD Dengue Vaccine or a Placebo	Within 14 days after injection	Solicited systemic reactions: Fever (Temperature), Headache, Malaise, Myalgia, and Asthenia. Grade 3 reactions: Fever, \>= 39°C; Headache, Malaise, Myalgia, and Asthenia, Significant, prevents daily activity.