Clinical Trials Register

Summary
EudraCT Number:	2011-004456-19
Sponsor's Protocol Code Number:	A3L21
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2012-04-10
Trial results	View 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

2011-004456-19

A.3

Full title of the trial

Phase III, open-label, multi-center booster vaccination study in toddlers who completed a three-dose primary series of the DTaP-IPV-Hep B-PRP-T combined vaccine or Infanrix hexa™ in Study A3L11.

A.3.1

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

Immunogenicity Study of the Antibody Persistence and Booster Effect of the DTaP-IPV-Hep B-PRP-T Combined Vaccine at 15 to 18 Months of Age Following a Primary Series of DTaP-IPV-Hep B-PRP-T or Infanrix hexa™ Administered at 2, 4, and 6 Months of Age in Healthy Mexican Infants

A.4.1

Sponsor's protocol code number

A3L21

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00654901

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/015/2012

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Sanofi Pasteur S.A
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Sanofi Pasteur S.A
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sanofi Pasteur SA
B.5.2	Functional name of contact point	Director, Clinical Development
B.5.3	Address:
B.5.3.1	Street Address	1541, Avenue Marcel Mérieux
B.5.3.2	Town/ city	Marcy l'étoile
B.5.3.3	Post code	69280
B.5.3.4	Country	France
B.5.4	Telephone number	33(0)4 37 37 58 53
B.5.5	Fax number	33(0)4 37 37 74 38
B.5.6	E-mail	eduardo.santos-lima@sanofipasteur.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	Hexaxim
D.3.2	Product code	DTaP-IPV-HepB-PRP-T vaccine
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	D
D.3.9.3	Other descriptive name	DIPHTHERIA TOXOID
D.3.9.4	EV Substance Code	SUB12489MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	T
D.3.9.3	Other descriptive name	TETANUS TOXOID
D.3.9.4	EV Substance Code	SUB12608MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	PT
D.3.9.3	Other descriptive name	PERTUSSIS TOXOID
D.3.9.4	EV Substance Code	SUB14817MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	FHA
D.3.9.3	Other descriptive name	PERTUSSIS FILAMENTOUS HAEMAGGLUTININ
D.3.9.4	EV Substance Code	SUB20298
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	IPV
D.3.9.3	Other descriptive name	POLIOVIRUS (INACTIVATED) TYPE 1 (MAHONEY STRAIN) PRODUCED ON VERO CELLS
D.3.9.4	EV Substance Code	SUB25669
D.3.10	Strength
D.3.10.1	Concentration unit	DAgU D antigen unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	IPV
D.3.9.3	Other descriptive name	POLIOVIRUS (INACTIVATED) TYPE 2 (MEF-1 STRAIN) PRODUCED ON VERO CELLS
D.3.9.4	EV Substance Code	SUB25670
D.3.10	Strength
D.3.10.1	Concentration unit	DAgU D antigen unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	8
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	IPV
D.3.9.3	Other descriptive name	POLIOVIRUS (INACTIVATED) TYPE 3 (SAUKETT STRAIN) PRODUCED ON VERO CELLS
D.3.9.4	EV Substance Code	SUB25671
D.3.10	Strength
D.3.10.1	Concentration unit	DAgU D antigen unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	32
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	Hep B
D.3.9.3	Other descriptive name	HEPATITIS B SURFACE ANTIGEN
D.3.9.4	EV Substance Code	SUB14083MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	HAEMOPHILUS TYPE B POLYSACCHARIDE CONJUGATED TO TETANUS TOXOID
D.3.9.4	EV Substance Code	SUB25275
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	12
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	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Prevention of infections caused by Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, poliovirus types 1, 2 and 3, prevention against invasive infections caused by Haemophilus influenzae type b and infection caused by hepatitis B virus

E.1.1.1

Medical condition in easily understood language

Active immunisation against diphtheria,tetanus, pertussis, hepatitis B, poliomyelitis and invasive infections caused by Haemophilus influenzae type b

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10021430
E.1.2	Term	Immunisation
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10036897
E.1.2	Term	Prophylactic vaccination
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	HLT
E.1.2	Classification code	10021431
E.1.2	Term	Immunisations
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	HLGT
E.1.2	Classification code	10043413
E.1.2	Term	Therapeutic procedures and supportive care NEC
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Immunogenicity
- To describe the antibody (Ab) persistence at 15 to 18 months of age for all valences following a three-dose primary series vaccination of either
DTaP-IPV-Hep B-PRP-T or Infanrix hexa™ at 2, 4 and 6 months of age in a subset of subjects.
- To describe the immunogenicity of a booster dose of DTaP-IPV-Hep B-PRP-T given at 15 to 18 months of age in a subset of subjects.

Safety
- To describe the safety profile after a booster dose of DTaP-IPV-Hep B-PRP-T given at 15 to 18 months of age.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Toddlers previously included in Study A3L11 who completed the three-dose primary series vaccination of either DTaP-IPV-Hep B-PRP-T or Infanrix hexa™ at 2, 4 and 6 months of age
2) Toddlers of 15 to 18 months (456 to 578 days) of age, inclusive
3) Informed Consent Form signed by at least one parent or legal representative and two mandatory witnesses
4) Able to attend all scheduled visits and to comply with all trial procedures

E.4

Principal exclusion criteria

1) Participation in another clinical trial in the 4 weeks preceding the booster vaccination
2) Planned participation in another clinical trial during the present trial period
3) Congenital or acquired immunodeficiency, immunosuppressive therapy such as long-term systemic corticosteroid therapy
4) Systemic hypersensitivity to any of the vaccine components or history of a life-threatening reaction to a vaccine containing the same substances
5) Chronic illness at a stage that could interfere with trial conduct or completion 6) Blood or blood-derived products received in the last 3 months
7) Any vaccination in the 4 weeks preceding the booster vaccination
8) Any vaccination planned until the next visit
9) History of documented pertussis, tetanus, diphtheria, poliomyelitis, Haemophilus influenzae type b or hepatitis B infection(s) (confirmed either clinically, serologically or microbiologically)
10) Administration of a vaccine against pertussis, tetanus, diphtheria, poliomyelitis, Haemophilus influenzae type b, and/or hepatitis B infection(s) since the end of participation in Study A3L11
11) Coagulopathy, thrombocytopenia or a bleeding disorder contraindicating intramuscular vaccination
12) Known maternal history of HIV, hepatitis B (HBsAg) or hepatitis C seropositivity.
13) Subjects with any related SAE that occurred following the three-dose primary series administration of the investigational vaccine or of the reference vaccine in Study A3L11
14) History of seizures
15) Febrile (temperature ≥38.0°C) or acute illness on the day of inclusion
16) Known contraindication to further vaccination with a pertussis vaccine, i.e.:
- Encephalopathy
- Temperature >40.0°C within 48 hours following a vaccine injection, not due to another identifiable cause during the primary series
- Inconsolable crying that occurred for >3 hours within 48 hours following vaccine injection during the primary series
- Hypotonic hyporesponsive episode within 48 hours following vaccine injection during the primary series
- Seizures with or without fever within 3 days following vaccine injection

E.5 End points

E.5.1

Primary end point(s)

Immunogenicity :
The following endpoints were to be used to assess the Ab persistence (for all valences) before the booster dose at Day 0 (V01) in a subset of approximately 300 subjects:
- Ab titers for each valence
- Ab titers above a cut-off:
- Anti-T Ab titers ≥0.01 IU/mL and ≥0.1 IU/mL
- Anti-D Ab titers ≥0.01 IU/mL and ≥0.1 IU/mL
- Anti-Hep B Ab titers ≥10 mIU/mL and ≥100 mIU/mL
- Anti-PRP Ab titers ≥0.15 μg/mL and ≥1.0 μg/mL
- Anti-polio titers ≥8 (1/dil)
The following endpoints were to be used to assess the booster responses at Day 30 (V02):
- Ab titers for each valence
- Ab titers above a cut-off:
- Anti-T Ab titers ≥0.01 IU/mL, ≥0.1 IU/mL, and ≥1.0 IU/mL
- Anti-D Ab titers ≥0.01 IU/mL, ≥0.1 IU/mL, and ≥1.0 IU/mL
- Anti-Hep B Ab titers ≥10 mIU/mL and ≥100 mIU/mL
- Anti-PRP Ab titers ≥0.15 μg/mL and ≥1.0 μg/mL
- Anti-polio titers ≥8 (1/dil)
- Anti-pertussis toxoid (PT) and anti-filamentous hemagglutinin (FHA) Ab titers
≥4-fold increase
- Individual titer ratio for each valence (V02/V01)
- Seroconversion for pertussis Ab (anti-acellular pertussis toxoid [anti-PT] and
anti-FHA) defined as:
- Anti-PT and anti-FHA ≥4-fold Ab titers increase from V01 to V02
Booster response to pertussis (PT and FHA) was defined as:
- Subjects whose pre-vaccination Ab concentrations were less than the Lower
Limit of Quantitation (<LLOQ) demonstrated a booster response if they had post-vaccination levels ≥4 x LLOQ
- Subjects whose pre-vaccination Ab concentrations were ≥LLOQ but <4 x LLOQ demonstrated a booster response if they had a four-fold response (i.e. post-/pre-vaccination ≥4)
- Subjects whose pre-vaccination Ab concentrations were ≥4 x LLOQ
demonstrated a booster response if they had a two-fold response (i.e. post-/pre-vaccination ≥2)

Safety/Reactogenicity :
- Occurrence, nature (Medical Dictionary for Regulatory Activities [MedDRA] preferred term [PT]), severity, duration, and relationship to vaccination for any unsolicited systemic adverse events (AEs) reported in the 30 minutes after the booster dose.
- Occurrence, time to onset, number of days of occurrence, and severity of solicited (prelisted in the subject diary and Case Report Form) injection site reactions and systemic reactions up to 7 days after the booster dose.
- Occurrence, nature (MedDRA PT), time to onset, duration, severity, and relationship to vaccination (for systemic AEs only) of unsolicited (spontaneously reported) AEs up to 30 days after the booster dose.
- Occurrence of any serious adverse events (SAEs) throughout the study (from V01 to 6 months after the booster vaccination).

E.5.1.1

Timepoint(s) of evaluation of this end point

Blood Sampling: in a subset of approximately 300 subjects, two blood samples of 5 mL each were to be collected: before the booster dose (BL1-V01) and 1 month later (BL2-V02).
All subjects were to be followed for safety for up to 6 months after the booster dose.

E.5.2

Secondary end point(s)

Not applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable

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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.2.3

Other

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

Mexico

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

end of the trial = LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

1190

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

1190

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Vulnerable pop (enfants): ICF signed by the subject's the parent(s)/legal representative (and by an independent witness if required by local regulations)

F.3.3.7

Others

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

1190

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Not applicable

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:	Mexico

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