Clinical Trials Register

Summary
EudraCT Number:	2016-004214-96
Sponsor's Protocol Code Number:	MEIN/15/Bil-PSR/002
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:	2018-02-22
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

2016-004214-96

A.3

Full title of the trial

Bilastine and inflammation: an explorative study in subjects affected by Parietaria J.-induced Rhinoconjunctivitis – The Bi-FLO study

BILASTINA E INFIAMMAZIONE: STUDIO ESPLORATIVO IN SOGGETTI AFFETTI DA RINOCONGIUNTIVITE INDOTTA DA PARIETARIA

A.3.1

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

Clinical trial to evaluate Bilastine in subjects affected by Parietaria J.-induced Rhinoconjunctivitis.

Studio clinico che valuta il farmaco bilastina nei soggetti affetti da rinocongiuntivite indotta da parietaria.

A.3.2

Name or abbreviated title of the trial where available

The Bi-FLO study

Studio Bi-FLO

A.4.1

Sponsor's protocol code number

MEIN/15/Bil-PSR/002

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	MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG SA
B.1.3.4	Country	Luxembourg
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	Menarini International Operations Luxembourg SA
B.4.2	Country	Luxembourg
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	OPIS s.r.l.
B.5.2	Functional name of contact point	Dipartimento Medico
B.5.3	Address:
B.5.3.1	Street Address	Palazzo Aliprandi, Via Matteotti 10
B.5.3.2	Town/ city	Desio
B.5.3.3	Post code	20832
B.5.3.4	Country	Italy
B.5.4	Telephone number	003903626331
B.5.5	Fax number	00390362633633
B.5.6	E-mail	osservatorio@opis.it

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	ROBILAS - 20 MG COMPRESSE 20 COMPRESSE IN BLISTER AL/AL
D.2.1.1.2	Name of the Marketing Authorisation holder	MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A.
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	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BILASTINA
D.3.9.1	CAS number	0202189-78-4
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	BILASTINA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
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.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	Allerkin test
D.2.1.1.2	Name of the Marketing Authorisation holder	Lofarma S.p.A.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Parietaria judaica e Parietaria officinalis
D.3.9.2	Current sponsor code	Parietaria judaica e Parietaria officinalis
D.3.10	Strength
D.3.10.1	Concentration unit	AU/ml allergy unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 40
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rhinoconjunctivitis induced by Parietaria J.

Rinocongiuntivite indotta da parietaria

E.1.1.1

Medical condition in easily understood language

Rhinoconjunctivitis induced by Parietaria J.

Rinocongiuntivite indotta da parietaria

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

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	10001728
E.1.2	Term	Allergic rhinoconjunctivitis
E.1.2	System Organ Class	100000004853

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to evaluate the effect of Bilastine on nasal inflammatory parameters (eosinophil cells) assessed by means of a nasal
scraping test following NPT after 7 ± 2 days of treatment vs baseline.

L’obiettivo primario è di valutare l’effetto di Bilastina sui parametri infiammatori nasali (eosinofili) determinato tramite scraping nasale successivo al test di provocazione dopo 7 ± 2 giorni di trattamento rispetto al basale.

E.2.2

Secondary objectives of the trial

- To evaluate the effect of Bilastine on nasal inflammatory parameters (neutrophil cells) evaluated with a nasal scraping test following NPT
after 7 ± 2 days of treatment vs baseline.
- To assess the effect of Bilastine on reducing symptoms during NPT using the Total Symptom Score (TSS) in subjects sensitized to Parietaria Judaica.
- To evaluate the effects of NPT with with the allergene parietaria judaica and parietaria officinalis (Allerkin® test) on nasal inflammatory parameters assessed by means of nasal Nitric Oxide
(NO) measurement, Fractioned Exhaled Nitric Oxide (FeNO) and acoustic rhinomanometry before and after treatment with Bilastine.

- Valutare l’effetto di Bilastina sui parametri infiammatori nasali (neutrofili) determinato tramite scraping nasale successivo al test di provocazione dopo 7 ± 2 giorni di trattamento rispetto al basale.
- Valutare l’effetto di Bilastina nella riduzione dei sintomi durante il test di provocazione utilizzando il punteggio TSS (Total Symptom Score) in soggetti sensibilizzati a Parietaria Judaica.
- Valutare gli effetti sul test di provocazione con l’allergene parietaria judaica e parietaria officinalis (test Allerkin®) sui parametri infiammatori determinati tramite misurazione nell’ossido nitrico (Nitric Oxide – NO) nasale, dell’ossido nitrico esalato frazionato (Fractioned Exhaled Nitric Oxide - FeNO) e tramite rinomanometria acustica prima e dopo il trattamento con Bilastina.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, aged 18-65 years.
2. A reliable history consistent with moderate to severe persistent rhinoconjunctivitis (sneezing, rhinorrhea, itchy nose, nasal blockage
and/or itchy eyes, red eyes, watering eyes and/or itchy ear/palate) on exposure to Parietaria J. for at least 2 years and that has required symptomatic treatment.
3. Mean Total Rhinoconjunctivitis Symptom Score (TSS) ≥10 from 4 nasal symptoms and non-nasal symptoms over last pollen season.

1. Sesso maschile o femminile, età 18-65 anni.
2. Anamnesi affidabile coerente con rino-congiuntivite allergica persistente da moderata a severa (starnuti, rinorrea, prurito nasale, ostruzione nasale e/o prurito agli occhi, occhi arrossati, lacrimazione e/o prurito alle orecchie/palato) all’esposizione a Parietaria Judaica da almeno 2 anni e che ha richiesto un trattamento sintomatico.
3. Punteggio TSS medio per la rino-congiuntivite ≥10 da 4 sintomi nasali e 4 sintomi non-nasali nella precedente stagione pollinica.

E.4

Principal exclusion criteria

1. Diagnosis of asthma requiring Global Initiative for Asthma (GINA) Step 3 (www.ginasthma.org) or higher treatment.
2. If asthmatic, a deterioration of asthma that resulted in emergency treatment or hospitalization in the 12 months before randomization, or a life-threatening asthma attack (e.g. one requiring intubation and mechanical ventilation) at any time in the past.
3. Use of any oral or parenteral corticosteroid at any time within 1 month prior to Screening.
4. Asthma requiring high-dose inhaled corticosteroids (ICS) or anti-IgE therapy within 6 months prior to Screening.
5. Forced expiratory volume in 1 second (FEV1) <80% of predicted, or other evidence of partly controlled or uncontrolled asthma.
6. Clinically significant confounding symptoms of allergy to relevant local seasonal allergens (e.g. tree, grass, mugwort or mold).
7. Immunosuppressive treatment within 3 months prior to Visit 1(except steroids for allergic and asthma symptoms).
8. Previous immunotherapy treatment with any Parietaria allergen product for more than 1 month within 5 years prior to screening.
9. Malignancy, autoimmune diseases, acute systemic disease.
10. Concomitant nasal diseases (chronic rhinosinusitis, nasal polyps, nasal turbinate hypertrophy).
11. Hypersensitivity to the active ingredients (bilastine, parietaria judaica, parietaria officinalis, naphazoline hydrochloride and salbutamol) or to excipients of the study treatments.
12. Patients at high risk of systemic reactions.
13. Patients with contraindications for adrenaline or other emergency room drugs.
14. Pregnancy or breastfeeding.
15. Women of childbearing potential (WOCBP), including peri-menopausal woman who had a menstrual period within 1 year, will not be allowed to participate in the study unless they use effective methods of contraception during the study period and for 4 weeks after study completion.

1. Diagnosi di asma che richiede un trattamento GINA (Global Initiative for Asthma) Step 3 (www.ginasthma.org) o superiore.
2. Se asmatico, peggioramento dell’asma che ha avuto come esito un trattamento di emergenza o un ricovero ospedaliero nei 12 mesi precedenti la randomizzazione, o un attacco d’asma che ha messo il paziente in pericolo di vita (ad es. un attacco d’asma che ha richiesto intubazione e ventilazione meccanica) in qualsiasi momento nel passato.
3. Utilizzo di qualsiasi corticosteroide orale o per via parenterale in qualsiasi momento nel mese precedente lo screening.
4. Asma che ha richiesto corticosteroidi per inalazione (Inhaled Corticosteroids – ICS) ad alte dosi o terapia anti-IgE nei 6 mesi precedenti lo screening.
5. Volume espiratorio forzato in 1 secondo (Forced expiratory volume in 1 second - FEV1) < 80% del valore predetto, o altra evidenza di asma non controllata o parzialmente controllata.
6. Sintomi confondenti clinicamente significativi di allergia ai relativi allergeni locali stagionali (ad es. alberi, erba, artemisia o muffa).
7. Trattamento immunosoppressore nei 3 mesi precedenti la Visita 1 (ad eccezione di steroidi per sintomi allergici e di asma).
8. Pregressa immunoterapia con qualsiasi prodotto allergene di Parietaria per più di 1 mese nei 5 anni precedenti lo screening.
9. Patologia maligna, malattia autoimmune, patologia sistemica acuta.
10. Patologie nasali concomitanti (rino-sinusite cronica, polipi nasali, ipertrofia dei turbinati nasali).
11. Ipersensibilità agli ingredienti attivi (bilastina, parietaria judaica, parietaria officinalis, nafazolina cloridrato e salbutamolo) o agli eccipienti dei trattamenti in studio.
12. Pazienti ad alto rischio di reazioni sistemiche.
13. Pazienti che presentano controindicazioni all’adrenalina o ad altri farmaci da pronto soccorso.
14. Gravidanza o allattamento.
15. Le donne potenzialmente fertili, incluse le donne in fase di peri-menopausa che hanno avuto un ciclo mestruale entro l’anno, non potranno partecipare allo studio a meno che non utilizzino metodi contraccettivi efficaci durante il periodo di studio e per 4 settimane dopo il completamento dello stesso.

E.5 End points

E.5.1

Primary end point(s)

Difference in the percentage of responders between the two treatment groups. Responders are defined as patients with a 1-point or more reduction in eosinophils cells’ grading, evaluated with nasal scraping, from baseline to end of treatment.

Differenza nella percentuale di pazienti responder nei due gruppi di trattamento. I pazienti responder sono definiti come i pazienti con una riduzione di 1 punto o più nella valutazione degli eosinofili determinata con lo scraping nasale, dal basale alla fine del trattamento.

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline to end of treatment.

Dal basale alla fine del trattamento.

E.5.2

Secondary end point(s)

Symptom improvement after nasal provocation test through TSS evaluation.

Miglioramento dei sintomi dopo il test di provocazione nasale tramite valutazione TSS.

E.5.2.1

Timepoint(s) of evaluation of this end point

During visit 2 and visit 3

Durante la visita 2 e la visita 3

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.5.1

Number of sites anticipated in the EEA

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

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

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

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

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

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

Yes

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

None

Nessuno

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

2017-01-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-02

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-01-30

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