Clinical Trials Register

Summary
EudraCT Number:	2009-013904-30
Sponsor's Protocol Code Number:	V111_04
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-07-17
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
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2009-013904-30

A.3

Full title of the trial

A Phase II, Open Label Study to Evaluate the Immunogenicity, Tolerability and Safety of a MF59-Adjuvanted, Inactivated Novel Swine Origin A/H1N1 Monovalent Subunit Influenza Virus Vaccine in Healthy Subjects Aged 18 Years and Above

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

V111_04

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	NOVARTIS VACCINES AND DIAGNOSTICS S.R.L.
B.1.3.4	Country	Italy
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Information not present in EudraCT
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Influenza, purified antigen
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	7.5
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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.IMP: 2
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	Yes
D.2.1.1.1	Trade name	AGRIPPAL S1*1SIR C/A 0,5ML 08-
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS VACCINES AND DIAG.Srl
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Influenza, purified antigen
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	15
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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

Evaluate the Immunogenicity, Tolerability and Safety of a MF59-Adjuvanted, Inactivated Novel Swine Origin A/H1N1 Monovalent Subunit Influenza Virus Vaccine in Healthy Subjects Aged 18 Years and Above

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	12.0
E.1.2	Level	LLT
E.1.2	Classification code	10022000
E.1.2	Term	Influenza

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the immunogenicity of one and two intramuscular (IM) injections of the MF59-adjuvanted H1N1sw monovalent influenza vaccine in adult and elderly subjects previously exposed to 2009/10 NH formulation of TIV and in those not yet vaccinated against seasonal influenza 2009/10, with respect to CHMP criteria. To evaluate immunogenicity of one and two IM injections of full and half dose of a H1N1sw monovalent influenza vaccine concomitantly administered with a single IM dose of a seasonal TIV in adult subjects not yet vaccinated against seasonal influenza 2009/10, with respect to CHMP criteria. To evaluate immunogenicity of a single IM injection of a seasonal TIV when concomitantly administered with one and two IM injections of full and half dose of a H1N1sw monovalent influenza vaccine in adult subjects not yet vaccinated against seasonal influenza 2009/10, with respect to CHMP criteria.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. For study Groups A and B : Males and females aged 18 years and above on the day of enrollment, who took part to the Agrippal S1 or Fluad trials (V71_10S and V70_9S, respectively) for the 2009/10 vaccine registration; For study Groups C to E: Males and females aged 18 years and above on the day of enrollment, not yet exposed to the current seasonal formulation (2009/10 for NH) of the influenza vaccines; 2. Individuals in good health as determined by medical history, physical examination and clinical judgment of the investigator; 3. Documented consent obtained after the nature of the study has been explained according to local regulatory requirements; 4. Individuals are able to comply with all study procedures and are available for all clinic visits scheduled in the study. 5. Willingness to allow for serum samples to be stored beyond the study period, for potential additional future testing to better characterize immune response.

E.4

Principal exclusion criteria

1. Individuals who are not able to comprehend and to follow all required study procedures for the whole period of the study or who do not consent to the retention of the subject�s serum samples after study completion; 2. Individuals with behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the subject`s ability to participate in the study; 3. Individuals with history or any illness that, in the opinion of the investigator, might interfere with the results of the study or pose additional risk to the subjects due to participation in the study; 4. Individuals who have had received an influenza vaccine for the 2009/10 NH influenza season (for subjects to be included in Groups C to E only) prior to Visit 1; 5. Individuals who have had documented confirmed or suspected influenza disease within 6 months prior to Day 1. 6. Receipt of another investigational agent within 4 weeks prior to enrollment, or before completion of the safety follow-up period in this or in another study; unwilling to refuse participation in another clinical study through the end of this study; 7. Individuals who received any other vaccines within 4 weeks prior to enrollment in this study or who are planning to receive any vaccine within 4 weeks from the study vaccines; 8. Individuals who have ever received blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation in the past 12 weeks; 9. Individuals with axillary temperature &#8805; 38.0 degrees Celsius (&#8805; 38.5C, if measured orally or rectally) within 3 days of intended study vaccination; 10. Known or suspected impairment/alteration of immune function, for example resulting from: a. receipt of immunosuppressive therapy such as systemic corticosteroids known to be associated with the suppression of hypothalamic-pituitary-adrenal (HPA) axis (15 mg/day of prednisone or its equivalent) or chronic use of inhaled high-potency corticosteroids (e.g. budesonide 800�g/day or fluticasone 750�g/day) within 60 days prior to Visit 1, b. cancer chemotherapy, c. receipt of immunostimulants within 60 days prior to Visit 1, d. receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within 3 months prior to Visit 1 or planned during the full length of the study, e. known HIV infection or HIV-related disease; 11. History of progressive or severe neurological disorders (including Guillain-Barre` syndrome and convulsions, but excluding febrile convulsions); 12. History of or clinically suspected developmental delay 13. Bleeding diathesis;

E.5 End points

E.5.1

Primary end point(s)

Immunogenicity Endpoints The measures for immunogenicity as determined by HI are as follows: 1. Geometric mean HI titer (GMT) on Day 1, Day 22, Day 29 and Day 43 2. Day 22/Day1, Day 29/Day1, Day 43/Day 1, Day 29/Day 22, and Day 43/Day 22, geometric mean ratio (GMR) of HI; 3. Percentage of subjects achieving a seroconversion or a significant increase (defined as: HI &#8805;1:40 for subjects negative at baseline [<1:10]; a minimum 4-fold increase in HI titer for subjects positive at baseline [HI&#8805;1:10]) on Day 22, Day 29 and Day 43; 4. Percentage of subjects with a HI titer &#8805;1:40 (i.e. seroprotection) on Day 1, Day 22, Day 29 and Day 43. Criteria for success as determined by HI: For the monovalent H1N1sw vaccine, the immunogenicity criteria for success, as determined by HI, related to the EMEA/CPMP/VEG/4717/2003-Rev.1 (pandemic guideline) and EMEA/CHMP/VWP/263499/2006 (pre-pandemic guideline) are: For adults subjects aged 18-60 years: The percentage of subjects with seroconversion or significant increase in HI antibody is > 40% The percentage of subjects achieving an HI titer &#8805;40 is > 70%. The GMR is >2.5 For elderly subjects aged &#8805;61 years: The percentage of subjects with seroconversion or at significant increase in HI antibody is > 30% The percentage of subjects achieving an HI titer &#8805;40 is > 60%. The GMR is >2.0 All three criteria should be met in each age group to fulfill regulatory requirements. For the trivalent seasonal vaccine, the immunogenicity criteria for success, as determined by HI, related to the CHMP/BWP/214/96 guideline, are the same as listed above. However it is sufficient that at least one criterion per each strain should be achieved to fulfil regulatory requirements. Safety Endpoints The safety of the study vaccine will be assessed based on number of subjects exposed and with reported local and systemic reactions, as well as the number of subjects with reported unsolicited adverse events per vaccine and age group. Solicited local reactions will include ecchymosis, erythema, induration, swelling and pain at injection site; solicited systemic reactions will include headache, arthralgia, chills, fatigue, malaise, myalgia, nausea, sweating, and fever. Where applicable, reactogenicity after each injection will be summarized according to the Brighton collaboration case definition [Bonhoeffer J et al. Vaccine 2009;27(16): 2282-8] (1). Unsolicited reactions will include all AEs, including all SAEs, onset of chronic diseases and AEs that lead to withdrawal from the study and will be collected for the entire study period (from Day 1 to Day 43).

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.3.1

Comparator description

- same IMP used at different dosage

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

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

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
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)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
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.4.1	In the member state	404

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2009-07-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-07-14

P. End of Trial
P.	End of Trial Status	Completed

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