Clinical Trials Register

Summary
EudraCT Number:	2013-003732-72
Sponsor's Protocol Code Number:	13IC0847
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-10-14
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

UK - MHRA

A.2

EudraCT number

2013-003732-72

A.3

Full title of the trial

Randomised placebo-controlled study of grass pollen allergen immunotherapy tablet (AIT) for seasonal rhinitis: time course of nasal, cutaneous and immunological outcomes

A.3.1

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

Study of effects of grass pollen allergen immunotherapy tablet (AIT) for hay fever

A.3.2

Name or abbreviated title of the trial where available

Grass Pollen Allergen Immunotherapy Tablet (AIT) Time Course Study

A.4.1

Sponsor's protocol code number

13IC0847

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	Imperial College London
B.1.3.4	Country
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	ALK Abello, Horsholm - Supply of IMP and placebo
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Imperial College London
B.5.2	Functional name of contact point	Nabila Youssouf
B.5.3	Address:
B.5.3.1	Street Address	Joint Research Office
B.5.3.2	Town/ city	Imperial College and Imperial College Healthcare
B.5.3.3	Post code	W6 8RF
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02033110206
B.5.5	Fax number	02033110203
B.5.6	E-mail	nabila.youssouf08@imperial.ac.uk

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	GRAZAX 75,000 SQ-T oral lyophilisate
D.2.1.1.2	Name of the Marketing Authorisation holder	ALK Abello S/A
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Grazax
D.3.4	Pharmaceutical form	Oral lyophilisate
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.3.9.4	EV Substance Code	AS1
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	Oral lyophilisate
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

Grass-pollen induced rhinoconjunctivitis (hay fever).

E.1.1.1

Medical condition in easily understood language

Hay fever

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

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 understand the time course of clinical and immunological actions of grass pollen allergen immunotherapy tablets in the treatment of seasonal allergic rhinitis.

E.2.2

Secondary objectives of the trial

We will assess a number of clinical and immunological effects of treatment at several time points during the study. Again, the main comparison will be after 12 months treatment and between active and placebo-treated participants. Furthermore, the healthy, atopic participants will serve as a control at 12 months. Assessment will include the following:

1. Measurement of the size (cross-sectional area in cm2) of local skin swelling caused by injection of purified grass pollen allergen into the skin of the forearm.

2. An average of hay fever symptoms and use of hay fever medications during the pollen season, as recorded by weekly diaries.

3. The results of immunological tests on blood, nasal fluid, nasal brushing and biopsy samples, such as the levels of ‘protective’ antibodies in blood serum.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Atopic participants:

1. Adults age 18 to 65 years.
2. A clinical history of grass pollen-induced allergic rhinoconjunctivitis for at least 2 years with peak symptoms in mid-May to mid-July.
3. A clinical history of moderate to severe rhino conjunctivitis symptoms with or without mild seasonal asthma interfering with usual daily activities or with sleep.
4. A clinical history of rhino conjunctivitis with or without mild seasonal asthma that remains troublesome despite treatment with either antihistamines or nasal corticosteroids during the grass pollen season.
5. Positive skin prick test response, defined as wheal diameter ≥ 3 mm, to timothy grass pollen.
6. Positive specific IgE, defined as IgE immunoCAP ≥ 0.7 ISU, against timothy grass pollen.
7. For women of childbearing age, a negative urine pregnancy test at the time of screening must be present and they should have expressed the willingness to use an effective form of contraception for the duration of involvement in the study.
8. The ability to give informed consent and comply with study procedures.
9. Nasal challenge with 5.000 BU/ml and consecutive Total nasal symptom score (TNSS) after 5 minutes ≥ 7/12.

Healthy, non-atopic participants:

1. Adults age 18 to 65 years.
2. Negative skin prick test response to timothy grass pollen and panel of aeroallergens.
3. Negative specific IgE, defined as IgE immunoCAP < 0.35 ISU, against timothy grass pollen.
4. For women of childbearing age, a negative urine pregnancy test at the time of screening and willingness to use an effective form of contraception for the duration of involvement in the study.
5. The ability to give informed consent and comply with study procedures.

E.4

Principal exclusion criteria

Atopic participants:

1. Previous grass pollen allergen immunotherapy.
2. Prebronchodilator FEV1 < 70% of predicted value at screening (out of grass-pollen season).
3. A clinical history of symptomatic allergic rhinitis and/or asthma caused by an allergen to which the participant is regularly and perennially exposed (e.g. cat dander).
4. Perennial asthma requiring regular inhaled corticosteroids.
5. Seasonal symptoms outside the grass-pollen season (e.g. March to April with sensitization to birch pollen giving a hint to symptomatic polyallergenic)
6. History of emergency visit or hospital admission for asthma in the previous 12 months.
7. History of chronic obstructive pulmonary disease.
8. History of significant recurrent acute sinusitis, defined as 2 episodes per year for the last 2 years, all of which required antibiotic treatment.
9. History of chronic sinusitis, defined as a sinus symptoms lasting greater than 12 weeks that includes 2 or more major factors or 1 major factor and 2 minor factors. Major factors are defined as facial pain or pressure, nasal obstruction or blockage, nasal discharge or purulence or discolored postnasal discharge, purulence in nasal cavity, or impaired or loss of smell. Minor factors are defined as headache, fever, halitosis, fatigue, dental pain, cough, and ear pain, pressure, or fullness.
10. At screening visit, current symptoms of, or treatment for, upper respiratory tract infection, acute sinusitis, acute otitis media, or other relevant infectious process; serous otitis media is not an exclusion criterion. Participants may be re-evaluated for eligibility after symptoms resolve.
11. Current smokers or a history of ≥ 5 pack years.
12. History of life-threatening anaphylaxis or angioedema.
13. Ongoing systemic immunosuppressive treatment.
14. The use of any investigational drug within 30 days of the screening visit.
15. The presence of any medical condition that the investigator deems incompatible with participation in the study.
16. History of fish allergy with positive skin test and/or positive specific IgE test to vertebrate/finned fish.

Non-atopic participants:

1. Previous grass pollen allergen immunotherapy.
2. Prebronchodilator FEV1 < 70% of predicted value at screening (out of grass-pollen season).
3. A clinical history of symptomatic allergic rhinitis and/or asthma caused by an allergen to which the participant is regularly and perennially exposed (e.g. cat dander).
4. Perennial asthma requiring regular inhaled corticosteroids.
5. Seasonal symptoms outside or during the grass-pollen season.
6. History of emergency visit or hospital admission for asthma in the previous 12 months.
7. History of chronic obstructive pulmonary disease.
8. History of significant recurrent acute sinusitis, defined as 2 episodes per year for the last 2 years, all of which required antibiotic treatment.
9. History of chronic sinusitis, defined as sinus symptoms lasting greater than 12 weeks that includes 2 or more major factors or 1 major factor and 2 minor factors. Major factors are defined as facial pain or pressure, nasal obstruction or blockage, nasal discharge or purulence or discolored postnasal discharge, purulence in nasal cavity, or impaired or loss of smell. Minor factors are defined as headache, fever, halitosis, fatigue, dental pain, cough, ear pain, pressure, or fullness.
10. At screening visit, current symptoms of, or treatment for, upper respiratory tract infection, acute sinusitis, acute otitis media, or other relevant infectious process; serous otitis media is not an exclusion criterion. Participants may be re-evaluated for eligibility after symptoms resolve.
11. Current smokers or a history of ≥ 5 pack years.
12. History of life-threatening anaphylaxis or angioedema.
13. Ongoing systemic immunosuppressive treatment.
14. The use of any investigational drug within 30 days of the screening visit.
15. The presence of any medical condition that the investigator deems incompatible with participation in the study.

E.5 End points

E.5.1

Primary end point(s)

We will use a well-established Questionnaire (Total Nasal Symptom Score, TNSS) to record nasal symptoms during the first 60 minutes after nasal allergen challenge (purified grass pollen sprayed into the nose). Specifically, we will look at whether the response to the allergen challenge is different in participants receiving active treatment compared to those receiving dummy treatment (placebo), after 12 months of treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

(please see above)

E.5.2

Secondary end point(s)

1. Cross-sectional area in cm2 of EPR and LPR skin responses to intradermal grass pollen allergen injection at 12 months in active versus placebo treated participants.

2. Mean combined symptom + medication scores over the course of the 2014 grass pollen season in active versus placebo-treated participants.

3. Serum and nasal fluid grass pollen specific IgG4 level and inhibition of B cell IgE-facilitated allergen binding in active versus placebo-treated patients versus non-atopic controls at 12 months.

4. Allergen-induced peripheral blood basophil activation in active versus placebo-treated participants versus non-atopic controls at 12 months.

5. Proportion of allergen-specific phenotypic Treg cells in peripheral blood as measured by flow cytometry in active vs placebo-treated patients versus non-atopic controls at 12 months.

Exploratory endpoints will include, in active versus placebo-treated patients versus non-atopic controls at 12 months: the frequency of putative Breg cells in peripheral blood; the molecular binding profiles of IgE and IgG4 antibodies; T and B cell receptor sequencing; frequency of putative type 2 innate lymphoid cells (ILC2s).

E.5.2.1

Timepoint(s) of evaluation of this end point

(please see above)

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

Yes

E.6.13.1

Other scope of the trial description

Explore mechanisms of immunotherapy

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

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.8.5

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

Last visit of last participant.

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