Clinical Trials Register

Summary
EudraCT Number:	2013-000617-20
Sponsor's Protocol Code Number:	SMART_2
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-04-16
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

Germany - PEI

A.2

EudraCT number

2013-000617-20

A.3

Full title of the trial

A Dose Finding Study of the Efficacy of LAIS® Mites Sublingual tablets in patients suffering from house dust mite-induced allergic rhinoconjunctivitis
A prospective, double-blind, placebo-controlled randomized multi-centre trial.

Dosisfindungsstudie zur Wirksamkeit von LAIS® Milben Tabletten bei Patienten mit durch Hausstaubmilben verursachter allergischer Rhinokonjunktivitis.
Eine prospektive, doppelblinde, placebo-kontrollierte randomisierte,
multi-zentrische klinische Studie.

A.3.1

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

A study which aims at finding an optimal dose and at evaluating the
efficacy of LAIS Mite Sublingual tablets in patients suffering from allergic
inflammation of the conjunctiva and rhinitis which are caused by house dust mite

A.4.1

Sponsor's protocol code number

SMART_2

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	Lofarma S.p.A.
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	Lofarma S.p.A.
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	Institut für Med. Statistik, Informatik u. Epidemiologie
B.5.2	Functional name of contact point	Coordinating Investigator
B.5.3	Address:
B.5.3.1	Street Address	Lindenburger Allee 42
B.5.3.2	Town/ city	Köln
B.5.3.3	Post code	50931
B.5.3.4	Country	Germany
B.5.4	Telephone number	00492214783456
B.5.5	Fax number	00492214783465
B.5.6	E-mail	informatik@imsie.de

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	Lais Mites Sublingual Tablets
D.3.2	Product code	Lais Mites Sublingual Tablets
D.3.4	Pharmaceutical form	Sublingual tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Sublingual use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lais Mites Sublingual Tablets
D.3.9.3	Other descriptive name	Chemically modified allergen extract of Dermatophagoides pteronyssinus (50%) and Dermatophagoides farina (50%)
D.3.10	Strength
D.3.10.1	Concentration unit	AgU antigen unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Sublingual tablet
D.8.4	Route of administration of the placebo	Sublingual use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients suffering from allergic rhinoconjunctivitis

E.1.1.1

Medical condition in easily understood language

Patients suffering from allergic inflammation of the conjunctiva and
rhinitis

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	16.1
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 efficacy of sublingual immunotherapy with the allergoid LAIS® Mites Sublingual tablets will be assessed by the mean improvement in the allergic severity S between baseline and visit V4,
comparing the five treatment groups.
Allergic severity S is rated by means of the severity stage integer values 0 ≤ ci ≤ 4. Here i is a number of an attempt (titration stage), made to reach a positive allergic reaction within the Conjunctival Provocation Test (CPT). CPT is considered positive if the response is stage 2 or higher.
The maximum number of attempts (N) is restricted with the titration solutions available. If the severity stage is reached to be ci= 2, the CPT is considered as positive, the test is stopped for the current visit and N is the number of steps to reach a positive result (1, 2, 3).
The titrated conjunctival allergen challenge will be conducted with solutions containing 100, 1,000 and 10,000 SQ-E/ml mite allergens.

E.2.2

Secondary objectives of the trial

· Physical examinations and the description of the adverse events (frequency, intensity, severity and duration of adverse events) during the treatment with LAIS® Mites Sublingual tablets
· Documentation of the safety of the treatment with LAIS® Mites Sublingual tablets.
· The changes of the threshold allergen concentration for a positive response within CPT will be compared for each of the five treatment groups. There will be three categories to detect the change in response threshold:
Improved: A higher allergen concentration is required to induce a positive CPT response.
Unchanged: The allergen concentration for a positive CPT is unchanged.
Worse: A lower allergen concentration induces a positive CPT response.
· Assessment of redness of the eye in CPT rated by a central observer

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

¨ Female or male patients aged 18–75 years with a history of at least two years of house dust mite (HDM) induced allergic rhinitis and/or allergic rhinoconjunctivitis with or without controlled asthma upon exposure to house dust mite [From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012. Available from: http://www.ginasthma.org]
¨ Clinically relevant sensitization to mites. Patients with clinically relevant sensitization to seasonal aero-allergens occurring during the study period, for example grass or rye may not be included.
Also patients with clinically relevant sensitization to perennial allergens like animal dander may not be included
¨ Positive clinical history of allergy due to house dust mite (HDM), proven by
o The majority of perennial clinical symptoms appearing mostly related to indoor mites allergens
o Specific IgE reactivity to mites allergens (CAP –radioallergosorbent test (CAP-RAST) ≥ 2
o Positive skin prick test (wheal diameter > 3mm, negative control < 2mm)
o Positive response to conjunctival provocation testing with at least 10,000 SQ-E/ml of mite allergens at both visits V0 AND V1. The conjunctival allergen challenge will be conducted with solutions containing 100, 1,000 and 10,000 SQ-E/ml mite allergens.
Additionally the difference in reacting concentration at visits V0 and V1 must not exceed one step of allergen concentration. Otherwise the test will be considered as irregular and the patient must be excluded.
In the case that there is a difference between the reactive concentrations at visit V0 and V1 the higher concentration will be assumed as baseline reactivity.
¨ Signed and dated patient’s Informed Consent
Special criteria for patients with co-sensitizations: for all patients with co-sensitizations all of the following inclusion criteria must be fulfilled:
¨ Patients do not suffer from typical symptoms against co-allergens
¨ Specific CAP-RAST results to co-allergenes less than the CAP-RAST result to mite allergens (the difference has to be ≥ 1), the patients with co-allergen against animal dander must not be exposed to the specific allergen
¨ The result of the skin prick test against co-allergenes is less than the result of the skin prick test against mites allergens

E.4

Principal exclusion criteria

¨ Simultaneous participation in other clinical trials
¨ Previous immunotherapy with mite allergens or cross reacting allergens within the last 5 years
¨ Ongoing immunotherapy with any allergen
¨ Patients being in any relationship or dependency with the sponsor and/or investigator
¨ Other reasons contra-indicating an inclusion into the trial according to the investigator’s estimation
(e.g. poor compliance, inability of the patient to understand study documents and instructions)
¨ Existing or intended pregnancy, lactation and/or lack of adequate contraceptive protection
¨ Predominant seasonal allergic rhinitis
¨ Partly controlled or uncontrolled asthma
¨ Chronic asthma or emphysema, particularly with a FEV <70% of the predicted value and /or <70%
of the individual optimum value
¨ Infections of the oral cavity with severe symptoms
¨ Patients with Galactose-intolerance, Lactase-deficiency, Glucose-Galactose-malabsorption
¨ Active tuberculosis
¨ Generally inflammatory as well as severe acute and chronic inflammatory diseases
¨ Irreversible secondary disorders at the target organ (e.g. emphysema, bronchoectasis)
¨ Immune deficiency (for example induced by immunosuppressive drugs)
¨ Physician diagnosed diseases of the liver, spleen, nervous system, thyroidal gland as well rheumatic diseases, based on an autoimmune mechanism,
¨ Malignancy
¨ Alcohol abuse as well as drug and / or medication abuse
¨ Patients treated with contra-indicated drugs
¨ Contra-indication for adrenalin (for example, acute or chronic symptomatic coronary heart disease, severe hypertension, hyperthyroidism)
¨ Completed or ongoing long-term treatment with tranquilizer or psycho active drugs
¨ Completed or ongoing treatment with anti-IgE-antibody

E.5 End points

E.5.1

Primary end point(s)

The efficacy of sublingual immunotherapy with the allergoid LAIS® Mites Sublingual tablets will be
assessed by the mean improvement in the allergic severity S between baseline and visit V4,
comparing the five treatment groups.
Allergic severity S is rated by means of the severity stage integer values 0 ≤ ci ≤ 4. Here i is a number
of an attempt (titration stage), made to reach a positive allergic reaction within the Conjunctival Provocation Test (CPT). CPT is considered positive if the response is stage 2 or higher.
The maximum number of attempts (N) is restricted with the titration solutions available. If the severity stage is reached to be ci= 2, the CPT is considered as positive, the test is stopped for the current visit and N is the number of steps to reach a positive result (1, 2, 3).
It is the aim of the trial to document that the mean allergic severity S of patients can be decreased by a 12 weeks course of SLIT.

E.5.1.1

Timepoint(s) of evaluation of this end point

day 0 and day 84 of the study

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit 0, Visit 1, Visit 2, Visit 3, and Visit 4

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

Yes

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

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

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

multi-centre

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

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

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

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.1.1.1

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:

120

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

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

150

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)

Patients will be treated after finishing the study according to the guidelines by their physicians.

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

2013-08-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-05-09

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