Clinical Trials Register

Summary
EudraCT Number:	2014-004431-38
Sponsor's Protocol Code Number:	Lais-Ragweed-15-16
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-01-28
Trial 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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2014-004431-38

A.3

Full title of the trial

Double-blind, placebo-controlled, parallel-group, randomized multicentre study to assess the efficacy and safety of LAIS® Ragweed Sublingual tablet in patients with allergic rhinoconjunctivitis to ragweed pollen

A.3.1

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

Efficacy and Safety of LAIS® in patients with allergic rhinoconjunctivitis to ragweed pollen

A.3.2

Name or abbreviated title of the trial where available

Lais-Ragweed-15

A.4.1

Sponsor's protocol code number

Lais-Ragweed-15-16

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	Lofarma
B.5.2	Functional name of contact point	Dr. Marco Bruno
B.5.3	Address:
B.5.3.1	Street Address	Via Cassala 40
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20142
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390258198211
B.5.5	Fax number	0039025819802
B.5.6	E-mail	marco.bruno@lofarma.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	LAIS® Ragweed
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	Hungary
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® Ragweed Maintenance Therapy
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	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	RAGWEED POLLEN
D.3.9.4	EV Substance Code	SUB49668
D.3.10	Strength
D.3.10.1	Concentration unit	AU/ml allergy unit(s)/millilitre
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 with allergic rhinoconjunctivities to ragweed pollen with or without asthma

E.1.1.1

Medical condition in easily understood language

Patients with allergic rhinoconjunctivities to ragweed pollen with or without asthma

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	17.1
E.1.2	Level	SOC
E.1.2	Classification code	10021428
E.1.2	Term	Immune system disorders
E.1.2	System Organ Class	10021428 - Immune system disorders

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 efficacy of a 4-5 months SLIT treatment with Ragweed monomeric allergoid (LAIS Ragweed) administered at 1000 UA/day in ragweed allergic patients with rhinoconjunctivitis with/or without concomitant asthma, due to ragweed pollen by means of the Total Combined Score (TCS).

E.2.2

Secondary objectives of the trial

Main secondary objective is to evaluate efficacy by means of:
-Six individual symptom scores of the Rhinoconjunctivitis Symptom
Score (RSS) for the period V2-V3.
-The Total Rhinoconjunctivitis Symptom Score (TRSS) for the period V2-
V3.
-The Total Rescue Medication Score (TRMS) for the period V2-V3.
-Number of well days (defined as days without intake of rescue
medication and symptom, score ≤2).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Female or male patients aged 18-75 years with a physician diagnosed history of at least two years of ragweed pollen induced allergic rhinitis and/or allergic rhinoconjunctivitis with/without seasonal allergic controlled asthma (level I-II of Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma).
•Clinically relevant sensitization to ragweed pollen.
•Positive clinical history of allergy due to ragweed pollen, proven by:
-Clinical symptoms appearing mostly related to ragweed allergens.
-Demonstration of a value of specific IgE to ragweed pollen (Amb a1> 2.5 KU/L) with ImmunoCAP test.
-Positive skin prick test for ragweed pollen (wheal diameter > 5mm, negative control < 2mm).
•Retrospective global symptoms score >8.
•Compliance and ability of the patient to complete a diary card for self-evaluation of the symptoms and anti-symptomatic medication.
•Availability to be present at the visits of the protocol for the duration of the study.
•Urinary negative pregnancy test (if women of childbearing age).
•Fertile women willing to use contraception.
•Women of childbearing potential that allow to use a highly effective method of birth control beginning to adopt at least one month prior to study enrollment and continuing to use it for the duration of the study.
•Signed and dated patient’s Informed Consent (subjects needed to be willing to give informed written consent and to adhere to dose and visit schedules).

E.4

Principal exclusion criteria

•Simultaneous participation in other clinical trials.
•Patients who had used any investigational drugs within 30 days of screening.
•Previous immunotherapy with ragweed allergens or cross reacting allergens within the last 5 years.
•Ongoing immunotherapy with any allergen.
•Subjects who are unlikely to be able to complete the trial or likely to travel for extended periods during the season (not exposed or low exposition during the last week of August and the first and second week of September).
•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).
•Predominant perennial allergic rhinitis.
•Patients with clinically relevant sensitization to other overlapping seasonal aero-allergens (alternaria, parietaria, etc), occurring during the ragweed season, cannot be included. In addition, patients with clinically relevant sensitization to perennial allergens like mites and animal dander of cat or dog (if living at home).
•Sensitization to wormwood with demonstration of specific IgE for Art v1 > 2.5 KU/L with ImmunoCAP test.
•Severe asthma, uncontrolled asthma or requiring daily continuative treatment with medium/high inhaled corticosteroids or bronchodilators.
•Lung function with a FEV <70% of the predicted value and /or <70% of the individual optimum value.
•Severe atopic dermatitis.
•Infections of the oral cavity.
•Rhino-sinusitis, rhinitis medicamentosa, polyposis.
•Patients with already diagnosed galactose-intolerance, lactase-deficiency, glucose-galactose-malabsorption or other malabsorption syndromes.
•History of anaphylaxis.
•Active tuberculosis.
•Diagnosed multi-systemic chronic autoimmune diseases.
•Diagnosed chronic disease involving lung (COPD, emphysema, bronchiectasis), heart (i.e. severe hypertension, heart failure, coronary disease), nervous system, thyroid, liver, spleen, kidney.
•Immune deficiency (for example induced by immunosuppressive drugs).
•Malignancy.
•Alcohol abuse as well as drug and/or medication abuse.
•Patients treated with drugs contra-indicated during immunotherapy.
•Contra-indication for adrenalin (subjects who are unable to or would not comply with the use of self-injectable epinephrine or are at a greater risk of developing adverse reactions after its use, or who have a history of self-injectable epinephrine use was ineligible).
•Completed or ongoing long-term treatment with tranquilizer or psycho active drugs.
•Subject who is breast-feeding, pregnant, or intend to become pregnant.
•Subjects who have any clinically significant condition or situation that the investigator judges would interfere with participation or study evaluations

E.5 End points

E.5.1

Primary end point(s)

To assess the efficacy of sublingual immunotherapy with the allergoid LAIS® Ragweed Sublingual tablets (between the visits V2 and V3, corresponding to the expected ragweed pollen exposition period).
The ragweed season is defined as beginning on the first of 3 consecutive recorded days with pollen count ≥10 grains/m3 and ending on the last day of the last occurrence of 3 consecutive days with pollen count ≥10 grains/m3. The analysis will be focused on the pollen peak defined as the 15 consecutive recorded days within the ragweed season with the highest 15-day moving average pollen count for each site. Pollen regions will be defined according to pollen stations and included sites within an acceptable distance from pollen counters (counters were within approximately 50 miles from the subject's home).

The efficacy analysis will be based on the assessment of a “Total Combined Score (TCS)“ for the peak pollen season taking into account:

•Total Rhino-conjunctivitis Symptom Score (TRSS), of the six rhino-conjunctivitis symptoms sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus/redness and watery eyes.
•Total Rescue Medication Score (TRMS), taking into account the use of oral antihistamines, antihistamine eye drops, nasal corticosteroids and oral/systemic corticosteroids.

The Total Combined symptoms-medication Score (TCS), calculated as: TCS = TRSS + TRMS (maximum score 36), of the pollen peak of the first pollen season will be the primary outcome

E.5.1.1

Timepoint(s) of evaluation of this end point

15 days

E.5.2

Secondary end point(s)

To assess the efficacy of a sublingual immunotherapy with the allergoid LAIS® Ragweed Sublingual tablets related to:
•The Total combined score (TCS) for the entire pollen season (entire diary-compiling period) of the year.
•Six individual symptom scores of the Rhinoconjunctivitis Symptom Score (TRSS) for the period V2-V3 during the 15-days peak and the entire diary-compiling period.
•The Total Rhinoconjunctivitis Symptom Score (TRSS) for the period V2-V3 during the 15-days peak and the entire diary-compiling period.
•The Total Rescue Medication Score (TRMS) for the period V2-V3 during the 15-days peak and the entire diary-compiling period.
•The number of well days, defined as days along the entire pollen season without intake of rescue medication and symptom score of 2 or less. The “hell days” are defined as days with TRSS ≥ 10 and additional use of rescue medication.
•Patients’ global evaluation: in order to permit a computation of a responder analysis, the rhinoconjuntivitis symptoms were globally evaluated at the end of the treatment period, by asking subjects the following question “Compared to your symptoms in previous ragweed seasons, how have you felt overall in this ragweed pollen season?” with possible response categories: much better-better-the same-worse-much worse (to be analysed as: much better, or better= improved; the same, worse, much worse= not improved).
•Visual analogue scale (VAS), filled in by patient, to assess the subjective overall wellbeing related to the allergic condition at the beginning and at the end of treatment period.
•Patients’ Quality of Life (Rhinoconjunctivitis Quality of Life Questionnaire-RQLQ) for the period V2-V3 will be evaluated before and at the end of the ragweed pollen season. [http://www.qoltech.co.uk/questionnaires.htm]
•Ragweed specific (Amb a1) IgE, and IgG4 serum levels and total IgE levels at the beginning (V0) and at the end of the pollen season (V3) i.e. the end of the study.
•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) during the treatment with LAIS® Ragweed Sublingual tablets.

E.5.2.1

Timepoint(s) of evaluation of this end point

5 months

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

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)

Yes

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

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

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

Yes

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

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.1.1.1

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:

200

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

156

F.4.2

For a multinational trial

F.4.2.1

In the EEA

228

F.4.2.2

In the whole clinical trial

228

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)

Treatment of care after the subject has ended the participation in the trial will be the normal treatment of that condition

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

2015-03-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-03-16

P. End of Trial
P.	End of Trial Status	Ongoing

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