Clinical Trials Register

Summary
EudraCT Number:	2022-003868-25
Sponsor's Protocol Code Number:	DEN-03-IB
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2024-04-22
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2022-003868-25

A.3

Full title of the trial

Double-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial to Evaluate the Efficacy and Safety of the Dengue 1,2,3,4 (Attenuated) Vaccine produced by Instituto Butantan

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Phase III Trial to Evaluate Efficacy and Safety of a Tetravalent Dengue Vaccine

A.4.1

Sponsor's protocol code number

DEN-03-IB

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02406729

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1168-8679

A.5.4

Other Identifiers

Name:

V181-004

Number:

Merck Sharp & Dohme LLC

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/521/2022

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Instituto Butantan
B.1.3.4	Country	Brazil
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Instituto Butantan
B.4.2	Country	Brazil
B.4.1	Name of organisation providing support	Merck Sharp & Dohme LLC
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck Sharp & Dohme LLC
B.5.2	Functional name of contact point	Maria Alejandra Esteves Jaramillo
B.5.3	Address:
B.5.3.1	Street Address	126 East Lincoln Avenue
B.5.3.2	Town/ city	P.O. Box 2000, Rahway, NJ,
B.5.3.3	Post code	07065
B.5.3.4	Country	United States
B.5.4	Telephone number	+1-267-305-2019
B.5.6	E-mail	alex.esteves@merck.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Dengue 1,2,3,4 (Attenuated) Vaccine
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.3	Other descriptive name	Live-attenuated Dengue (serotype 4) rDENV4Δ30
D.3.9.4	EV Substance Code	SUB206689
D.3.10	Strength
D.3.10.1	Concentration unit	PFU/dose plaque forming unit(s)/dose
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10E+3
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	Live-attenuated Dengue (serotype 1), rDENV1Δ30
D.3.9.4	EV Substance Code	SUB206687
D.3.10	Strength
D.3.10.1	Concentration unit	PFU/dose plaque forming unit(s)/dose
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10E+3.0
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	Live-attenuated (chimeric) Dengue (serotype 2), rDENV2/4Δ30(ME)
D.3.9.4	EV Substance Code	SUB206686
D.3.10	Strength
D.3.10.1	Concentration unit	PFU/ml plaque forming unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10E+3.0
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	Live-attenuated Dengue (serotype 3), rDENV3Δ30/31
D.3.9.4	EV Substance Code	SUB206688
D.3.10	Strength
D.3.10.1	Concentration unit	PFU/dose plaque forming unit(s)/dose
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10E+3.0
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	Yes
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Lyophilisate for solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Dengue

E.1.1.1

Medical condition in easily understood language

Prevention of dengue

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10012309
E.1.2	Term	Dengue
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To evaluate the overall efficacy of a single dose of the Dengue 1,2,3,4 (attenuated) vaccine produced by Instituto Butantan containing 103 PFU of each vaccine virus against virologically confirmed symptomatic dengue 28 days after vaccination in subjects ranging from 2 to 59 years of age, regardless of their prior exposure to dengue viruses.
2. To describe the onset of adverse reactions associated with administration of a single dose of Dengue 1,2,3,4 (attenuated) Vaccine produced by Instituto Butantan containing 103 PFU of each vaccine virus up to 21 days post-vaccination in subjects from 2 to 59 years of age, regardless of their prior exposure to dengue viruses.

E.2.2

Secondary objectives of the trial

1. Evaluate efficacy of a single dose of the Dengue 1,2,3,4 (attenuated) Vaccine against symptomatic infection 28 days after vaccination with respect to prior exposure to dengue viruses.
2. Evaluate efficacy of a single dose of the Dengue 1,2,3,4 (attenuated) Vaccine against symptomatic infection 28 days after vaccination with respect to the four dengue serotypes.
3. Evaluate efficacy of a single dose of the Dengue 1,2,3,4 (attenuated) Vaccine 28 days after vaccination with respect to the onset of laboratory-confirmed dengue with warning signs and severe dengue.
4. Describe adverse reactions within the first 21 days post-vaccination.
5. Evaluate the immune response 4 weeks after vaccination with 3 consecutive batches of dengue 1, 2, 3, 4 (attenuated) vaccine in a subject subgroup with no prior exposure to dengue.
6. Evaluate the immune response 4 weeks after vaccination with batches produced with the simplified formulation in subjects with no prior exposure to dengue.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Characterization of Immune response.

E.3

Principal inclusion criteria

1. Children who have completed 24 months of age, adolescents and adults who have not completed 60 years of age;
2. Agree with periodic contacts, either/or by phone, electronic means, and home visits.
3. Show voluntary intention to participate in the study, documented by the participant's or participant's legal representative's signature of the informed consent form.

E.4

Principal exclusion criteria

1. For women: Pregnancy (confirmed by positive beta-hCG test) or breastfeeding;
2. Evidence of active neurological, cardiac, pulmonary, hepatic or renal disease as per clinical history and/or physical examination;
3. Compromised immune system diseases including: decompensated diabetes mellitus, cancer (except basal cell carcinoma), congenital or acquired immune deficiencies and not controlled autoimmune, as per clinical history and/or physical examination;
4. 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;
5. Abusive usage of alcohol or drugs in the past 12 months that has caused medical, professional or family problems, indicated by clinical history;
6. History of severe allergic reactions or anaphylaxis to the vaccine or to components of the vaccine in study;
7. History of asplenia;
8. Use of any investigational product within 28 days before or after receiving this study vaccination;
9. Has participated in another clinical trial six months prior to inclusion in the study or planning to participate in another clinical trial within 2 years following inclusion;
10. Use of immunosuppressant drugs such as: antineoplastic chemotherapy, radiation therapy, immunosuppressants to induce tolerance to transplants, and corticosteroids use (except topical or nasal). For this protocol will be considered for exclusion use of corticosteroids 3 months prior to the inclusion in the study and 6 months prior to the inclusion for the other therapies mentioned, and planned use of any immunosuppressant therapy within 2 years following inclusion in the study. It will be considered immunosuppressive dose of corticosteroids the equivalent to a dose ≥20 mg of prednisone per day for adults and the equivalent of prednisone at 2 mg/kg/day for children for over 7 days;
11. Have received blood products in the past three months, including transfusions or immunoglobulin, or scheduled administration of blood products or immunoglobulin for the following 2 years after vaccination;
12. Fever or suspected fever within 72 hours prior to vaccination or axillary temperature greater than 37,8°C on the day of vaccination (inclusion might be postponed until participant has completed 72 hours of no fever);
13. 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 28 days after receiving the investigational product;
14. 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.

E.5 End points

E.5.1

Primary end point(s)

1. Efficacy (incidence density of symptomatic dengue cases, virologically confirmed)
2. Safety (adverse reactions)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Five years post vaccination, all cases after 28 days post-vaccination
2. In the first 21 days post-vaccination

E.5.2

Secondary end point(s)

1. Efficacy (incidence density of dengue cases confirmed virologically, regarding previous exposure to dengue viruses. )
2. Efficacy (incidence density of dengue cases confirmed virologically, regarding the viral serotype)
3. Efficacy (incidence density of cases of severe dengue and/or with alarm signs, including cases hospitalized or not)
4. Safety ( frequency of solicited and unsolicited local and systemic adverse reactions in participants regarding previous exposure to dengue viruses )
5. Safety (frequency of unsolicited adverse reactions)
6. Immunogenicity (consistency of the immune response to different batches of the vaccine )
7. Immunogenicity (non-inferiority between simplified formulation vs. conventional formulation)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. at five years post vaccination, all cases after 28 days post-vaccination
2. Five years post vaccination, all cases after 28 days post-vaccination
3. Five years post vaccination, all cases after 28 days post-vaccination
4. Time Frame: In the first 21 days post-vaccination
5. Five years post vaccination, all cases after the first 21 days post-vaccination
6. 4 weeks post vaccination
7. 4 weeks post vaccination

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

Brazil

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last data generated

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	Yes
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	Yes
F.1.1.6	Adolescents (12-17 years)	Yes
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	Yes
F.3.2	Patients	No
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.2	For a multinational trial
F.4.2.2	In the whole clinical trial	16235

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	Brazil

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