Clinical Trials Register

Summary
EudraCT Number:	2013-005550-30
Sponsor's Protocol Code Number:	SB/0042
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-04-15
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2013-005550-30

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled (DBPC), parallel group study to assess the clinical efficacy and safety of SUBLIVAC FIX Birch immunotherapy in patients suffering from allergic rhinitis/rhinoconjunctivitis caused by birch pollen followed by an optional open label, one group safety-extension period. SB/0042 study

A.3.1

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

Study to assess the clinical efficacy and safety of SUBLIVAC FIX Birch immunotherapy in patients with allergic rhinitis/rhinoconjunctivitis caused by birch pollen

A.3.2

Name or abbreviated title of the trial where available

SUBLIVAC FIX Birch Phase III short-term efficacy

A.4.1

Sponsor's protocol code number

SB/0042

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	HAL Allergy B.V.
B.1.3.4	Country	Netherlands
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	HAL Allergy B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	HAL Allergy B.V.
B.5.2	Functional name of contact point	Clinical Trial Management
B.5.3	Address:
B.5.3.1	Street Address	J.H. Oortweg 15-17
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 CH
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+ 31881959165
B.5.5	Fax number	+ 31881959001
B.5.6	E-mail	dboot@hal-allergy.com

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	SUBLIVAC FIX Birch 40.000 AUN/ml
D.3.2	Product code	SUBLIVAC FIX Birch
D.3.4	Pharmaceutical form	Oromucosal drops
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	Allergen extract of Betula verrucosa
D.3.9.2	Current sponsor code	SUBLIVAC FIX BIRCH
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40.000
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	Oromucosal drops
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

Moderate to severe birch pollen induced allergic rhinitis/rhinoconjunctivitis with or without mild to moderate persistent asthma.

E.1.1.1

Medical condition in easily understood language

Birch allergy.

E.1.1.2

Therapeutic area

Diseases [C] - Ear, nose and throat diseases [C09]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10001726
E.1.2	Term	Allergic rhinitis due to pollen
E.1.2	System Organ Class	100000004870

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary Objective:
To assess clinical efficacy of sublingual immunotherapy with SUBLIVAC FIX Birch (40.000 AUN/ml), compared to placebo, in patients suffering from birch pollen induced rhinitis/rhinoconjunctivitis, measured by a combined rhinoconjunctivitis symptoms score and medication score during the birch pollen season.

E.2.2

Secondary objectives of the trial

• To assess clinical efficacy of sublingual immunotherapy with SUBLIVAC
FIX Birch during the peak pollen season compared to placebo
• To assess the effect of sublingual immunotherapy with SUBLIVAC FIX
Birch on Quality of Life (QoL) during the pollen season compared to
placebo
• Changes in serum specific immunoglobulin levels after treatment with
sublingual immunotherapy with SUBLIVAC FIX Birch compared to
placebo
•To assess the effect of sublingual immunotherapy with SUBLIVAC FIX
Birch on the percentage of responders compared to placebo

Safety objectives:
• Safety and tolerability of sublingual immunotherapy with SUBLIVAC
FIX Birch compared to placebo
•Safety and tolerability of sublingual immunotherapy with SUBLIVAC FIX
Birch for 6 months during the Safety-Extension period

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent
2. Age ≥ 18 and ≤65 years
3. Moderate-to-severe birch pollen induced allergic rhinitis/rhinoconjunctivitis based on ARIA classification for at least 2 consecutive years
4. FEV1 > 70% (of predicted value) for patients with a history of asthma, FEV1 > 70% or PEF > 80% (of predicted value) for patients without a history of asthma
5. Positive SPT for birch pollen (mean wheal diameter ≥ 3mm compared to negative control; negative control should be negative; histamine control should be positive (mean wheal diameter ≥ 3mm)) assessed during screening.
6. Serum specific anti-birch IgE concentration >0.7 U/ml

Inclusion criteria to be assessed at Visit 2 before randomisation:
7. Patients should be willing and capable to complete an e-diary daily during the birch pollen season (≥ 60% compliance in completion between Visit 1 and 2).
8. A positive Nasal Provocation Test to birch pollen (per appendix 3) at Visit 2 (Lebel score ≥ 6) or a documented positive test within 1 year before start of treatment

Inclusion criteria for Safety-Extension period:
1 Signed updated informed consent including Safety-Extension period details
2 Patients that completed the double blind period of the study

E.4

Principal exclusion criteria

1. Patients sensitized and symptomatic to pets should not be included if they are regularly exposed to pets
2. Specific immunotherapy (SCIT or SLIT) with birch pollen or a cross-reacting allergen within the last 5 years
3. SPT positive (mean wheal diameter ≥ 3mm compared to negative
control; negative control should be negative; histamine control should be
positive (mean wheal diameter ≥ 3mm)) patients to allergen(s) other
than birch pollen, in the absence of a negative provocation test for this
allergen(s) (within 1 year), who are expected to have clinically relevant
symptoms during the birch pollen season
4. Completed unsuccessful allergen-specific immunotherapy (SCIT or SLIT) within the last 5 years
5. (Ongoing) allergen-specific immunotherapy (SCIT or SLIT) with any allergen(s) during the study period
6. Vaccination one week before start of treatment and/or during the up-dosing phase
7. Treatment with experimental products within the last 3 months or biologicals (including anti-IgE or TNF- α treatment) within the last 6 months or during the study
8. Uncontrolled asthma or other active respiratory diseases
9. Clinically significant chronic sinusitis, ocular infection or severe inflammation of the oral mucosa
10. Severe immune disorders (including auto-immune diseases) and/or diseases requiring immunosuppressive drugs
11. Active malignancies or any malignant disease in the last 5 years
12. Acute or chronic disease that in the opinion of the investigator is an additional risk for the patients, including but not limited to the following: cardiovascular insufficiency, any severe or unstable lung diseases, endocrine disorders, clinically significant renal or hepatic diseases, or haematological disorders
13. Diseases with a contra-indication for the use of adrenaline (e.g. hyperthyroidism, glaucoma)
14. Use of systemic corticosteroids 4 weeks before the study
15. Treatment with systemic or local β-blockers
16. Known hypersensitivity to any of the excipients (Disodium phosphate dihydrate, Sodium dihydrogen phosphate dehydrate, Aminocaproic acid, Peppermint oil, Caramel Colorant or Glycerol)
17. A positive urine pregnancy test, lactation or inadequate contraceptive methods (adequate methods: oral contraceptives, IUD, condom use and having no sexual relationship with a man)
18. Alcohol-, drug or medication abuse
19. Lack of co-operation or compliance
20. Severe psychiatric, psychological, or neurological disorders
21. Any physical or mental condition that precludes administration or allergen-specific immunotherapy, compliance or participation in a clinical trial
22. Patients who are employees of the department, 1st grade relatives, or partners of the investigator
23. Patients who have planned holidays outside the country for more than 7 continuous days during the defined pollen season (1st of March till 31st of May)

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the difference in mean Combined Symptom
Medication Score (CSMS) between the active vs. placebo treatment
group, assessed during birch pollen season.

E.5.1.1

Timepoint(s) of evaluation of this end point

During Birch pollen season (e-diary)

E.5.2

Secondary end point(s)

The secondary endpoints of the study are:
1. Difference in mean CSMS between the active vs. placebo treatment group, assessed during the birch peak pollen season
2. Difference in daily Symptom Score (dSS) assessed during the birch (peak) pollen season between the active vs. placebo treatment group.
3. Difference in daily Medication Score (dMS) assessed during the birch (peak) pollen season in the active vs. placebo treatment group.
4. Difference between active and placebo treatment in Quality of Life (QoL) during the birch pollen season and End Of Treatment (EOT), determined by standardized (rhinoconjunctivitis) QoL questionnaire (RQLQ-S and EQ-5D) for all patients and for patients with birch pollen induced concomitant asthma by an additional asthma control
questionnaire (ACQ)
5. Differences in serum specific immunoglobulin levels (IgE, IgG, IgG4) in the active vs. placebo treatment group after treatment.
6. Differences in number of 'well days' and 'severe days' between the active and placebo treatment
The exploratory endpoint of the study is:
7. Difference in mean CSMS between the active and placebo treatment group using the placebo score-based period.
Safety endpoints:
8. Safety assessed by local and systemic reactions, (serious) adverse events, blood safety biochemistry/haematology parameters, urinalysis, vital signs and ECG in the active treatment vs. placebo group before, during and after treatment.
9. Safety and tolerability of sublingual immunotherapy with SUBLIVAC FIX Birch for 6 months during the Safety-Extension period of the study assessed by (serious) adverse events, physical examination and vital signs.

E.5.2.1

Timepoint(s) of evaluation of this end point

Endpoints no 1, 2, 3: birch peak pollen season
Endpoint 4: during the birch pollen season and at the End Of Treatment (EOT),
Endpoint 5: after treatment
Endpoint 6: during the birch pollen season
Endpoint 7: placebo score-based period (four weeks with the highest CSMS reported
in the placebo group determined per site)
Endpoint 8: before ( Visit 1), during (Visits 5 ) and after treatment (Visit 8)
Endpoint 9: Over 6 mo period after completion of the double blind phase

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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

Yes

E.8.1.7.1

Other trial design description

double-blind, placebo-controlled parallel group followed by open label, one group safety period

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:

360

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

400

F.4.2.2

In the whole clinical trial

400

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)

After completion of the study, patients will be offered to continue treatment with SUBLIVAC FIX Birch (40.000 AUN/ml) in 6-mo extension safety study. At the end of the study visit (visit 9), patients will be asked to participate in an extension safety study and will sign a
separate informed consent for this purpose. If allowed following local country regulations, patients will receive SUBLIVAC FIX Birch (40,000
AUN/ml) as post-study medication after completion of the Safety Extension period.

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

2014-05-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-06-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-02-03

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