Clinical Trials Register

Summary
EudraCT Number:	2010-021235-13
Sponsor's Protocol Code Number:	SP/0036
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:	2012-05-21
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

2010-021235-13

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled study to determine safety, tolerability and the optimal effective dose of SUBLIVAC FIX Phleum pratense in patients with allergic rhinitis/rhinoconjunctivitis caused by grass pollen

A.3.1

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

A clinical study to determine a safe and optimal effective dose of SUBLIVAC FIX Phleum pratense for reducing allergy symptoms

A.3.2

Name or abbreviated title of the trial where available

SUBLIVAC FIX Phleum pratense DT/DRF

A.4.1

Sponsor's protocol code number

SP/0036

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	+ 31881959105
B.5.5	Fax number	+ 31881959001
B.5.6	E-mail	evtwuijver@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 Phleum Pratense 3.333 AUN/ml
D.3.2	Product code	SUBLIVAC FIX Phleum Pratense
D.3.4	Pharmaceutical form	Oromucosal drops
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oromucosal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	allergen extract from Phleum Pratense pollen
D.3.9.2	Current sponsor code	SUBLIVAC FIX Phleum pratense (3.333 AUN/ml)
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.333
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.IMP: 2
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 Phleum Pratense 10.000 AUN/ml
D.3.2	Product code	SUBLIVAC FIX Phleum Pratense
D.3.4	Pharmaceutical form	Oromucosal drops
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oromucosal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	allergen extract from Phleum Pratense pollen
D.3.9.2	Current sponsor code	SUBLIVAC FIX Phleum pratense (10.000 AUN/ml)
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10.000
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.IMP: 3
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 Phleum Pratense 20.000 AUN/ml
D.3.2	Product code	SUBLIVAC FIX Phleum pratense
D.3.4	Pharmaceutical form	Oromucosal drops
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oromucosal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	allergen extract from Phleum pratense pollen
D.3.9.2	Current sponsor code	SUBLIVAC FIX Phleum pratense (20.000 AUN/ml)
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20.000
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.IMP: 4
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 Phleum pratense 40.000 AUN/ml
D.3.2	Product code	SUBLIVAC FIX Phleum pratense
D.3.4	Pharmaceutical form	Oromucosal drops
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oromucosal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	allergen extract from Phleum pratense pollen
D.3.9.2	Current sponsor code	SUBLIVAC FIX Phleum pretense (40.000 AUN/ml)
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	Oromucosal 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 rhinitis/rhinoconjunctivitis related to grass pollen (with or without concomitant mild to moderate persistent asthma).

E.1.1.1

Medical condition in easily understood language

Grass 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	15.1
E.1.2	Level	LLT
E.1.2	Classification code	10001723
E.1.2	Term	Allergic rhinitis
E.1.2	System Organ Class	100000004855

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:
Determination of the optimal effective dose of SUBLIVAC FIX Phleum pratense based on reduction of upper airways reactivity assessed by TNPT after 5 months of treatment with different dosages of SUBLIVAC FIX Phleum pratense compared to placebo.
Co-primary Objective:
Difference in proportions of patients not reaching maintenance dose within 10 days due to related AEs of different dosages of SUBLIVAC FIX Phleum pratense compared to placebo.

E.2.2

Secondary objectives of the trial

- Safety and tolerability of different dosages of SUBLIVAC FIX Phleum pratense compared to placebo assessed by local and systemic reactions.
- Changes in serum specific immunoglobulin levels after 5 months of treatment with different dosages of SUBLIVAC FIX Phleum pratense compared to placebo.
- Changes in PNIF after 5 months of treatment with different dosages of SUBLIVAC FIX Phleum pratense compared to placebo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent
2. Age ≥18 ≤ 60 years
3. Allergic rhinitis/rhinoconjunctivitis related to grass pollen with or without concomitant mild to moderate persistent asthma
4. FEV1>70% for patients with a history of asthma, FEV>70% or PEF>80% for patients without a history of asthma
5. A positive SPT (mean wheal diameter ≥ 3mm compared to negative control and negative control should be negative) for grass pollen assessed within 1 year before randomization.
6. Positive serum specific anti-grass IgE-test (>0.7 U/mL)
7. A positive TNPT for grass pollen at screening (Lebel score ≥6) at ≤10,000 AU/mL

E.4

Principal exclusion criteria

1. Patients with (expected) clinically relevant symptoms during the course of the trial due to concomitant sensitization i.e. positive SPT (mean wheal diameter ≥ 3mm) to allergens other than grass pollen
2. Patients sensitized to pets should not be included if they are regularly exposed to pets and are symptomatic upon exposure to pets
3. Completed immunotherapy (SCIT or SLIT) with grass pollen allergens within the past 5 years
4. Completed unsuccessful specific immunotherapy in the past
5. Vaccination within one week before start of therapy or during the initiation phase
6. Anti-IgE therapy within the 6 months prior to inclusion and during the study
7. Severe immune disorders (including auto-immune diseases) and/or diseases requiring immunosuppressive drugs
8. Active malignancies or any malignant disease during the previous 5 years
9. Severe uncontrolled diseases that could increase the risk for patients participating in the study, including but not limited to: cardiovascular insufficiency, any severe or unstable lung diseases, endocrine diseases, clinically significant renal or hepatic diseases, or haematological disorders
10. Active inflammation or infection of the target organs (nose, eyes or lower airways) at the start of the study
11. Moderate to severe nasal obstructive diseases that preclude a TNPT (septal deviation, nasal polyps, recent nasal surgery, etc.)
12. Diseases with a contraindication for the use of Adrenaline (e.g. hyperthyroidism, glaucoma)
13. Use of systemic steroids within 4 weeks before start of the study and during the study
14. Treatment with systemic and local β-blockers
15. Participation in a clinical study with a new investigational drug within the last 3 months or for a biological within the last 6 months prior to or during the study
16. Pregnancy, lactation or inadequate contraceptive measures for women of child-bearing age (adequate contraceptive measures will be the use of a contraceptive device or –pill)
17. Alcohol, drug or medication abuse within the past year
18. Any clinically significant abnormal laboratory parameter at screening
19. Lack of cooperation or compliance
20. Severe psychiatric, psychological, or neurological disorders
21. Patients who are employees of the institution or 1st grade relatives or partners of the investigator

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the absolute difference in mean total symptom score in the TNPT between 5 months of treatment and baseline. The differences in mean symptom score of the active dose groups and placebo will be compared in a step-down pairwise comparison starting with the highest dose.

E.5.1.1

Timepoint(s) of evaluation of this end point

Timepoint for primary end point - after 5 months of treatment.

E.5.2

Secondary end point(s)

Safety and tolerability of different dosages of SUBLIVAC FIX Phleum pratense vs. placebo will be assessed by number and severity of immediate and delayed local and systemic reactions.
Immunogenicity of different dosages of SUBLIVAC FIX Phleum pratense (vs. placebo) after 5 months of treatment will be determined by serum specific immunoglobulin levels. At baseline and the end of the study visit a blood sample will be drawn for determination of specific IgE, IgG and IgG4 to grass. Changes in specific immunoglobulin levels before and after 5 months of treatment will be determined
Changes in PNIF as a parameter of nasal patency will be determined following TNPT in patients receiving different dosages of SUBLIVAC FIX Phleum pratense compared to placebo

E.5.2.1

Timepoint(s) of evaluation of this end point

After 5 months of treatment.

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

Yes

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)

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

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

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

Work of investigators with study data is ending by answering last queries.
Thus, end of clinical trial was defined as Database lock.
In general, following prerequisites for database lock are given:
- Queries returned, processed and entered
- Coding completed/reviewed
- Review of data by statistician (protocol violations, relevant adverse events)
- All automatic batches related to study deactivated
When these requirements are fulfilled it is considered as end of clinical part.

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:

250

F.1.3

Elderly (>=65 years)

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

120

F.4.2

For a multinational trial

F.4.2.1

In the EEA

250

F.4.2.2

In the whole clinical trial

250

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 the study all participants will be offered to complete a full course
of treatment free of charge (3 years in total)

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

2012-09-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-08-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-05-15

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