Clinical Trials Register

Summary
EudraCT Number:	2012-000063-24
Sponsor's Protocol Code Number:	V71_32S
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-03-19
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

2012-000063-24

A.3

Full title of the trial

A Phase II, Open Label, Uncontrolled, Multi Center Study to Evaluate Safety & Immunogenicity of AGRIPPAL S1 Vaccine, Formulation 2012-2013, in Non-elderly Adult and Elderly Subjects

Studio multicentrico, non controllato, in aperto, di fase II per la valutazione della sicurezza e dell immunogenicita' di un vaccino antinfluenzale (Agrippal), antigene inattivato, di superficie, formulazione 2012/2013, quando somministrato a soggetti adulti e anziani

A.3.1

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

Clinical Trial to evaluate the safety and antibody response of Agrippal flu vaccine for the 2012/2013 flu season

Studio Clinico per valutare la sicurezza e la risposta anticorpale del vaccino antinfluenzale Agrippal per la stagione influenzale 2012/2013

A.3.2

Name or abbreviated title of the trial where available

V71_32S

A.4.1

Sponsor's protocol code number

V71_32S

A.7

Trial is part of a Paediatric Investigation Plan

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	NOVARTIS VACCINES AND DIAGNOSTICS S.R.L.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NOVARTIS VACCINES AND DIAGNOSTICS S.R.L.
B.5.2	Functional name of contact point	Clinical Research Development SE
B.5.3	Address:
B.5.3.1	Street Address	FIORENTINA, 1
B.5.3.2	Town/ city	Siena
B.5.3.3	Post code	53100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0577 539177
B.5.5	Fax number	0577 278491
B.5.6	E-mail	sperclin_seuropa.nvdit@novartis.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	Yes
D.2.1.1.1	Trade name	AGRIPPAL S1*1SIR S/A 0,5ML 11-
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	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
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 VACCINE (SURFACE ANTIGEN, INACTIVATED)
D.3.9.1	CAS number	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB12067MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	45
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

Clinical trial on healthy volunteers: prophylaxis of influenza, especially in subjects with a higher risk of flu associated complications.

Sperimentazione su volontari sani: profilassi dell’influenza, specialmente nei soggetti che corrono maggiore rischio di complicazioni associate.

E.1.1.1

Medical condition in easily understood language

Prophylaxis of influenza in elderly and adults at risk

Prevenzione dell'influenza in anziani e adulti a rischio

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

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	10022000
E.1.2	Term	Influenza
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

To evaluate the safety of a single intramuscular (IM) injection of Agrippal in adult and elderly subjects. in compliance with the requirements of the current EU recommendations for clinical trials related to yearly licensing of influenza vaccines (CPMP/BWP/214/96). To evaluate the antibody response to each influenza vaccine antigen, as measured by Single Radial Hemolysis (SRH) at approximately 21 days post-immunization in adult and elderly subjects.

Valutare la sicurezza di un’unica iniezione intramuscolare (IM) di Agrippal nei soggetti adulti e anziani in conformità ai requisiti delle raccomandazioni europee attuali per gli studi clinici riguardanti l’autorizzazione annuale dei vaccini antinfluenzali (CPMP/BWP/214/96). Valutare la risposta anticorpale di ciascun antigene del vaccino antinfluenzale nei soggetti adulti e anziani, misurata mediante emolisi radiale singola (SRH) 21 giorni dopo l’immunizzazione,

E.2.2

Secondary objectives of the trial

Antibodies maybe additionally quantified using the hemagglutination inhibition (HI) test for confirmation purposes (Note for Guidance on Harmonization of Requirements for Influenza Vaccines CPMP/BWP/214/96: 12 March 1997).

Ai fini di conferma è possibile quantificare gli anticorpi anche mediante il test dell’inibizione dell’emoagglutinazione (HI) (Note for Guidance on Harmonization of Requirements for Influenza Vaccines. CPMP/BWP/214/96: 12 marzo 1997).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male and female volunteers of 18 years of age or older, mentally competent, willing and able to give written informed consent prior to study entry; Individuals able to comply with all the study requirements; Individuals in good health as determined by the outcome of medical history, physical examination and clinical judgment of the investigator.

1. Volontari di sesso maschile e femminile di età non inferiore a 18 anni, capaci di intendere e di volere e di consegnare il consenso informato scritto prima dell'inclusione nello studio. 2. Individui capaci di soddisfare tutti i requisiti dello studio. 3. Individui in buona salute, come risulta dall'anamnesi, dagli esami fisici e dal giudizio clinico dello sperimentatore.

E.4

Principal exclusion criteria

Individuals with behavioral or cognitive impairment or psychiatric disease. Individuals with any serious chronic or acute disease (in the judgment of the investigator). Individuals with history of any anaphylactic reaction and/or serious allergic reaction following a vaccination, a proven hypersensitivity to any component of the study vaccine. Individuals with known or suspected (or have a high risk of developing) impairment/alteration of immune function. Individuals with known or suspected history of drug or alcohol abuse. Individuals with a bleeding diathesis or conditions associated with prolonged bleeding time. Individuals who are not able to comprehend and to follow all required study procedures for the whole period of the study. Individuals with history or any illness that, in the opinion of the investigator, pose additional risk to the subjects due to participation in the study. Individuals who within the past 6 months have: - had any laboratory confirmed seasonal or pandemic influenza disease; - received any seasonal or pandemic influenza vaccine. Individuals who received any other vaccine within 4 weeks prior to enrollment in this study or who are planning to receive any vaccine during the study. Individuals with any acute or chronic infections requiring systemic antibiotic treatment or antiviral therapy within the last 7 days. Individuals that have experienced fever (i.e., axillary temperature ≥ 38°C) within the last 3 days of intended study vaccination. Individuals participating in any clinical trial with another investigational product 4 weeks prior to first study visit or intent to participate in another clinical study at any time during the conduct of this study. Individuals who are part of study personnel or close family members conducting this study. BMI > 35 kg/m2. Females who are pregnant (confirmed by positive urine pregnancy test) or nursing (breastfeeding). Females of childbearing potential4 who refuse to use an acceptable method of birth control for the whole duration of the study.

Individui affetti da disturbi cognitivi o patologie psichiatriche Individui con patologie acute o croniche gravi. Individui con anamnesi positiva per reazioni anafilattiche e/o reazioni allergiche gravi in seguito a una vaccinazione, ipersensibilità nota a un componente del vaccino oggetto di studio. Individui con noti o sospetti (oppure con un elevato rischio di sviluppare) disturbi o alterazioni della funzione immunitaria Individui con anamnesi nota o sospetta di abuso di alcol o droghe. Individui con una diatesi emorragica o condizioni associate a un tempo di sanguinamento. Individui che non sono in grado di comprendere e seguire tutte le procedure dello studio. Individui con un’anamnesi o patologia che, potrebbe porre ulteriori rischi per i soggetti a causa della partecipazione allo studio. Individui che, nel corso degli ultimi 6 mesi, hanno: avuto un’influenza pandemica o stagionale, confermata dagli esami di laboratorio;ricevuto un vaccino antinfluenzale pandemico o stagionale. Individui che hanno ricevuto qualsiasi altro vaccino entro le 4 settimane precedenti l'arruolamento o che hanno in programma di ricevere un qualsiasi altro vaccino durante il corso dello studio. Individui con infezioni croniche o acute che hanno richiesto un trattamento antibiotico sistemico o una terapia antivirale negli ultimi 7 giorni. Individui che hanno avuto febbre (es. temperatura ascellare ≥ 38°C) nei 3 giorni precedenti la vaccinazione oggetto di studio. Individui che hanno partecipato a uno studio clinico con un altro prodotto sperimentale nelle 4 settimane precedenti la prima visita dello studio o che intendono partecipare a un altro studio clinico in qualsiasi momento durante il presente studio. Soggetti che fanno parte del personale del presente studio o che hanno stretti legami di parentela con il personale dello studio stesso IMC > 35 kg/m2. Donne in gravidanza (confermata positivamente attraverso un test di gravidanza delle urine) o in corso di allattamento. Donne in età fertile che non intendono utilizzare misure contraccettive accettabili, per l’intera durata dello studio.

E.5 End points

E.5.1

Primary end point(s)

Safety will be assessed in accordance with available safety data on influenza vaccines: -Local and systemic reactions will be assessed for 3 days post the day of vaccination - AEs Days 1 to 4. From Day 5 to study end AEs necessitating a physician’s visit or consultation and/or leading to premature study discontinuation and SAEs The following serological assessments will be considered for each strain in non-elderly adult subjects, aged between 18 and 60, and at least one of the assessments should meet the indicated requirements: - The proportion of subjects achieving seroconversion or significant increase in HI titer or SRH area >40% - Mean geometric increase >2.5 - The proportion of subjects achieving an HI titer ≥40 or SRH area ≥25 mm2 should be >70% The following serological assessments will be considered for each strain in elderly subjects, aged 60 years and over, and at least one of the assessments should meet the indicated requirements: - Proportion of seroconversion or significant increase in HI titer or SRH area >30% - Mean geometric increase >2.0 - The proportion of subjects achieving an HI titer ≥40 or SRH area ≥25 mm2 should be > 60% Circulating anti-HA antibodies will be measured by SRH and possibly HI assay just prior to vaccination (Day 1) and approximately 3 weeks after the vaccination (Day 22). For the purposes of calculation, any HI result <10 (i.e. undetectable) will be expressed as 5, and any negative SRH result will be expressed as 4 mm2. In HI tests, seroconversion or significant increase in antibody titer corresponds to: -negative pre-vaccination serum / post-vaccination serum titer ≥40 or -at least a four-fold increase in titer from positive pre-vaccination serum. In SRH tests, seroconversion or significant increase in antibody titer corresponds to: -negative pre-vaccination serum / post-vaccination serum area ≥25 mm2 -at least a 50% increase in area from positive pre-vaccination serum

La sicurezza verrà valutata in conformità con i dati disponibili sulla sicurezza relativamente ai vaccini antinfluenzali: • Le reazioni sistemiche e locali saranno valutate per 3 giorni dopo il giorno della vaccinazione • Gli eventi avversi dal Giorno 1 al 4. Dal Giorno 5 fino alla fine dello studio saranno valutati tutti gli eventi avversi che necessitano una visita o una consultazione medica e/o conducono ad una prematura uscita dallo studio, e tutti gli eventi avversi seri. Nei soggetti adulti non anziani, di età compresa tra 18 e 60 anni verranno considerate per ciascun ceppo le valutazioni sierologiche descritte di seguito, delle quali almeno una deve soddisfare i requisiti indicati: - Percentuale dei soggetti che raggiungono la sieroconversione o incremento significativo del titolo di HI o dell’area SRH > 40% - Incremento geometrico medio > 2,5 - La percentuale dei soggetti che raggiungono un titolo di HI ≥ 40 o area SRH ≥ 25 mm2 deve essere > 70% Nei soggetti anziani, di età almeno pari a 60 anni, verranno considerate per ciascun ceppo le valutazioni sierologiche descritte di seguito, delle quali almeno una deve soddisfare i requisiti indicati:: - Percentuale della sieroconversione o incremento significativo del titolo di HI o area SRH > 30% - Incremento logaritmico medio > 2,0 - La percentuale dei soggetti che raggiungono un titolo di HI ≥ 40 o area SRH ≥ 25 mm2 deve essere > 60% Gli anticorpi anti-HA in circolazione verranno misurati mediante SRH e, possibilmente, tramite test di HI immediatamente prima della vaccinazione (Giorno 1) e circa 3 settimane dopo la vaccinazione (Giorno 22). Ai fini del calcolo, tutti gli esiti del titolo di HI < 10 (cioè non rilevabile) verranno espressi come 5 mm2, mentre gli esiti negativi dell'SRH verranno espressi come 4 mm2. Nei test di HI, la sierconversione o un incremento significativo del titolo anticorpale corrisponde a: • titolo sierico pre-vaccinazione / post-vaccinazione negativo ≥ 40 oppure • un incremento di almeno quattro volte del titolo rispetto al siero prevaccinazione positivo Nei test dell’SRH, la sierconversione o un incremento significativo del titolo anticorpale corrisponde a: area del siero pre-vaccinazione / post-vaccinazione negativo ≥ 25 mm2 • un incremento di almeno il 50% dell’area rispetto al siero pre-vaccinazione positivo.

E.5.1.1

Timepoint(s) of evaluation of this end point

21 days after vaccination

21 giorni dopo la vaccinazione

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

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

E.8.1.2

Open

Yes

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.2.4

Number of treatment arms in the trial

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

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

LVLS

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

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)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

126

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)

All AEs will be monitored until resolution or, if the AE becomes chronic, a cause identified. If an AE is unresolved at the conclusion of the study, a clinical assessment will be made by the investigator and medical monitor whether continued follow-up of the AE is warranted.

Tutti gli AE saranno monitorati sino alla risoluzione o, nel caso diventino cronici, sino alla identificazione della causa. Se alla fine dello studio un AE è ancora non risolto, lo sperimentatore ed il medico del promotore effettueranno una valutazione clinica sevl'AE necessita di essere ancora seguito.

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

2012-01-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-03-08

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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