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    Summary
    EudraCT Number:2013-002129-43
    Sponsor's Protocol Code Number:SMART_7
    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:2013-08-12
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2013-002129-43
    A.3Full title of the trial
    Efficacy and Safety of sublingual immunotherapy with Allergoid LAIS®Birch-Alder tablets for patients with tree pollen-induced allergic rhinoconjunctivitis
    A Phase III study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study, which aims to evaluate the efficacy and safety of LAIS® Birch-Alder tablets in patients suffering from allergic inflammation of the conjunctiva and rhinitis caused by birch pollen
    A.4.1Sponsor's protocol code numberSMART_7
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/143/2011
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLofarma S.p.A.
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLofarma S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstitut für Med. Statistik, Informatik u. Epidemiologie
    B.5.2Functional name of contact pointCoordinating investigator
    B.5.3 Address:
    B.5.3.1Street AddressLindenburger Allee 42
    B.5.3.2Town/ cityKöln
    B.5.3.3Post code50931
    B.5.3.4CountryGermany
    B.5.4Telephone number+492214783456
    B.5.5Fax number+492214783465
    B.5.6E-mailinformatik@imsie.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLAIS Birch-Alder tablets
    D.3.2Product code LAIS Birch-Alder tablets
    D.3.4Pharmaceutical form Sublingual tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLAIS Birch-Alder tablets
    D.3.9.3Other descriptive nameChemically modified allergen extracts (monomeric allergoids) of tree pollen (Betula Pendula 50% and Alnus Incana 50%)
    D.3.10 Strength
    D.3.10.1Concentration unit AgU antigen unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSublingual tablet
    D.8.4Route of administration of the placeboSublingual use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients suffering from allergic rhinoconjunctivitis
    E.1.1.1Medical condition in easily understood language
    Patients suffering from allergic inflammation of the conjunctiva and rhinitis
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10001728
    E.1.2Term Allergic rhinoconjunctivitis
    E.1.2System Organ Class 100000004853
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to assess the efficacy of sublingual immunotherapy with the allergoid LAIS® Birch-Alder tablets by the Total Combined Score (TCS) taking in account the Rhinoconjuncticitis Total Symptom Score (RTSS) of the six rhinoconjunctivitis symptoms (sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus and watery eyes and the Total Rescue Medication Score (TRMS) for the peak of the birch pollen season.
    E.2.2Secondary objectives of the trial
    o TCS: a) for the birch pollen season of 30 days and b) for the entire tree pollen season of 60 days
    o Six individual symptom scores: a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days
    o RTSS: a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days
    o TRMS: a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days
    o Asthma rescue medication for the tree pollen season of 60 days
    o The mean improvement in the allergic severity S between baseline and visit V5
    o The changes of the threshold allergen concentration for a positive response within conjunctival provocation test (CPT)
    o The “well days”
    o Birch pollen specific IgG4
    o A global evaluation
    o Quality of Life
    o The rhinitis symptom control
    • Safety of the treatment
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Female or male patients aged 18–75 years with a history of at least two years of tree pollen induced allergic rhinitis and/or allergic rhinoconjunctivitis with or without seasonal controlled allergic asthma [From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012. Available from: http://www.ginasthma.org]
    •Clinical sensitization to tree pollen. Patients with sensitization to perennial allergens like mites, cats and dogs may be included, in the case that these sensitizations are not clinically relevant during the evaluation season
    •Positive clinical history of tree pollen, proven by:
    -the majority of clinical symptoms appearing during the appropriate season for tree,
    -specific IgE reactivity to tree pollen CAP-radioallergoabsorbent test (CAP-RAST) ≥ 2 (0.70 kU/L)
    -positive screening Skin Prick Test (wheal diameter > 3 mm, negative control < 2 mm)
    -Positive response to conjunctival provocation testing with at least 10,000 SQ-E/ml of tree 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 tree 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.
    •planned antiallergic or antiasthmatic treatment with the following drugs: local Levocabastine (eye), Loratadine (oral), Beclomethasone (nasal) or inhaled corticosteroids with long-acting ß2-agonists
    •Compliance and ability of the patient to complete a diary card for self-evaluation of the symptoms and antisymptomatic medication
    •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 coseasonal prevalent allergens
    •Specific CAP-RAST results to coseasonal prevalent allergens less than the CAP-RAST result to tree pollen (the difference has to be ≥ 1), the patients with coseasonal prevalent allergies against animal dander must not be exposed to the specific allergen
    •The result of the Skin Prick Test against co-allergens is less than the result of the Skin Prick Test against tree
    E.4Principal exclusion criteria
    •Simultaneous participation in other clinical trials
    •Previous immunotherapy with birch-alder allergens or cross-reacting allergens within the last 5 years
    •Ongoing immunotherapy for any allergen
    •Patients being in any relationship or dependency with the sponsor and/or investigator
    •Other reasons contraindicating 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 (see Annex XX.3)
    •Predominant perennial allergic rhinitis
    •Partly controlled or uncontrolled asthma
    •Chronic asthma or emphysema, particularly with a FEV <70% of the predicted value and/or PEF <70% of the individual optimum value
    •Infections of the oral cavity with severe symptoms
    •Patients with Galactose-intolerance, Lactase-deficiency, Glucose-Galactose-malabsorption
    •Patients with nasal abnormalities and/or polyps
    •Active tuberculosis
    •Generally inflammatory as well severe acute and chronic inflammatory diseases
    •Immune deficiency (for example induced by immunosuppressive drugs)
    •Auto-immune disorders
    •Physician diagnosed diseases of the liver, spleen, nervous system, thyroidal gland as well as rheumatic diseases, based on an autoimmune mechanism
    •Malignancy
    •Alcohol abuse as well as drug and/or medication abuse
    •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
    •Patients treated with contra-indicated drugs.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective is to assess the efficacy of sublingual immunotherapy with the allergoid LAIS® Birch-Alder tablets by the Total Combined Score (TCS) taking in account the Rhinoconjuncticitis Total Symptom Score (RTSS) of the six rhinoconjunctivitis symptoms (sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus and watery eyes and the Total Rescue Medication Score (TRMS) for the peak of the birch pollen season.
    E.5.1.1Timepoint(s) of evaluation of this end point
    14 days of highest birch pollen count in each region, the peak period of the birch pollen season
    E.5.2Secondary end point(s)
    • To assess the efficacy of a sublingual immunotherapy with the allergoid LAIS® Birch-Alder tablets related to
    o The Total Combined Score (TCS): a) for the birch pollen season of 30 days and b) for the entire tree pollen season of 60 days (March to April)
    o Six individual symptom scores of the Rhinoconjunctivitis Total Symptom Score (RTSS): a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days (March to April)
    o The Rhinoconjunctivitis Total Symptom Score (RTSS): a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days (March to April)
    o The Total Rescue Medication Score (TRMS): a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days (March to April),
    o The use of asthma rescue medication for the tree pollen season of 60 days (March to April)
    o The mean improvement in the allergic severity S between baseline and visit V5 within the conjunctival provocation test will be compared for both treatment groups.
    o The changes of the threshold allergen concentration for a positive response within conjunctival provocation test (CPT) will be compared for both treatment groups, according to the evaluation defined by Riechelmann H et al (2003) between baseline and visit V5.
    o The “well days”, being defined as days of the entire tree pollen season with a maximum symptom score of 2 and no rescue medication use according to Dahl (2006) and Durham (2006)
    o Assessment of birch pollen specific IgG4
    o A global evaluation carried out by the patient for the total tree pollen season
    o To evaluate the Quality of Life by the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)
    o The rhinitis symptom control will be compared by RCAT between both treatment groups at the end of the tree pollen season

    • To document the safety of the treatment by the physical examinations, the description of the adverse events (frequency, intensity, severity and duration of adverse events) and the safety laboratory data during the treatment with LAIS® Birch-Alder tablets.
    E.5.2.1Timepoint(s) of evaluation of this end point
    as specified in E.5.2
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned22
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state240
    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
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-12-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-10-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-07-29
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