Clinical Trials Register

Summary
EudraCT Number:	2014-002047-18
Sponsor's Protocol Code Number:	SM/0044
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:	2014-10-16
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

2014-002047-18

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled study to determine tolerability and safety of different dosages of SUBLIVAC FIX Mite mixture in patients with allergic rhinitis / rhinoconjunctivitis caused by house dust mites.

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 tolerable dose of SUBLIVAC FIX Mite mixture for reducing allergy symptoms

A.3.2

Name or abbreviated title of the trial where available

SUBLIVAC FIX Mite Mixture Dose Tolerability study

A.4.1

Sponsor's protocol code number

SM/0044

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	Medical Director
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	+ 31881959004
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 Mite Mixture 10.000 AU/mL
D.3.2	Product code	SUBLIVAC FIX Mite Mixture
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	House Dust Mites allergen extract
D.3.9.2	Current sponsor code	SUBLIVAC FIX Mite mixture
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	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: 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 Mite Mixture 25.000 AU/mL
D.3.2	Product code	SUBLIVAC FIX Mite Mixture
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	House Dust Mites allergen extract
D.3.9.2	Current sponsor code	SUBLIVAC FIX Mite mixture
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	25.000
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 Mite Mixture 50.000 AU/mL
D.3.2	Product code	SUBLIVAC FIX Mite Mixture
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	House Dust Mites allergen extract
D.3.9.2	Current sponsor code	SUBLIVAC FIX Mite mixture
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	50.000
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 Mite Mixture 100.000 AU/mL
D.3.2	Product code	SUBLIVAC FIX Mite Mixture
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	House Dust Mites allergen extract
D.3.9.2	Current sponsor code	SUBLIVAC FIX Mite mixture
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	100.000
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

Patients, 18-60 years of age, suffering from house dust mites-induced persistent allergic rhinitis/rhinoconjunctivitis with or without concomitant at least partly controlled asthma.

E.1.1.1

Medical condition in easily understood language

HDM induced 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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10020419
E.1.2	Term	House dust mite allergy
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

Determination of the tolerability and safety by local and systemic reactions of different SUBLIVAC FIX Mite mixture dosages during 1 month of treatment in patients with HDM induced allergic rhinitis/rhinoconjunctivitis in comparison with placebo

E.2.2

Secondary objectives of the trial

•Safety determined by reported adverse events during 1 month of SUBLIVAC FIX Mite mixture treatment compared to placebo.
• Safety determined by clinical and laboratory parameters assessed after 1 month of SUBLIVAC FIX Mite mixture treatment compared to placebo.
• Immunogenic activity determined by changes in serum specific immunoglobulin levels (IgE, IgG, IgG4) compared to screening assessed after 1 month of SUBLIVAC FIX Mite mixture treatment compared to placebo.
• Determine the proportion of patients in the different treatment groups reaching maintenance dose within 10 days

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Signed informed consent
2. Male or female patients, age≥18≤ 60 years
3. Patients with allergic rhinitis or rhinoconjunctivitis induced by HDM for at least 1 year, with or without concomitant at least partly controlled asthma
4. Patients with a history of concomitant asthma should have a FEV1 > 70% (of predicted value) at inclusion. Patients without a history of asthma should have a FEV1 > 70% or a PEF > 80% (of predicted value)
5. Positive SPT to HDM D. pter or D. far (mean wheal diameter ≥ 3 mm compared to negative control; negative control should be negative; histamine control should be positive (mean wheal diameter≥ 3 mm) at screening
6. Allergen specific serum IgE (ssIgE) level in serum for HDM D. pter or D. far (> 0.7 U/ml), assessed at screening

E.4

Principal exclusion criteria

1.Patients with concomitant sensitization i.e. positive SPT (mean wheal diameter ≥ 3 mm compared to negative control; negative control should be negative; histamine control should be positive (mean wheal diameter ≥ 3 mm) who are expected to have clinically relevant symptoms during the treatment period
2. Patients sensitized and symptomatic to pets who are regularly exposed to pets
3. Completed allergen-specific immunotherapy (SCIT or SLIT) with HDM within the last 5 years
4. Completed unsuccessful allergen-specific immunotherapy (SCIT or SLIT) within the last 5 years
5. Allergen-specific immunotherapy (SCIT or SLIT) with other allergens than HDM during the study period
6. Any other vaccination one week before start of treatment and during the up-dosing phase
7. Any anti-IgE therapy within the last 6 months prior to inclusion and during study
8. Active inflammatory disease in the mouth (e.g periodontitis, oral mucosal lichen planus)
9. Known hypersensitivity to any of the excipients (i.e. Disodium phosphate dihydrate, Sodium dihydrogen phosphate dihydrate, Aminocaproic acid, Glycerol, Peppermint oil, Caramel Colorant) of SLIT solution
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. A chronic or acute disease that in the opinion of the investigator might place the patient at an additional risk, 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 start treatment
15. Treatment with systemic or local b-blockers
16. Clinically significant chronic sinusitis or ocular infection
17. Participation in a clinical study with a new investigational drug within the last 3 months or a biological within the last 6 months prior to the study or during the study
18. Pregnancy, lactation or inadequate contraceptive measures (acceptable forms of birth control include Intrauterine devices or hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or long-acting injections) or condom combined with a diaphragm including spermicidal cream. Also acceptable for women is surgical sterilization (removal of the uterus or ovaries or tubal ligation (”tied tubes”)), if they are postmenopausal (12 consecutive months without a period) for at least 2 years or having no sexual relationship with a man.
19. Alcohol, drug, or medication abuse within the past year and during the study
20. Any lack of co-operation or compliance
21. Severe psychiatric, psychological, or neurological disorders
22. Patients who are employees of the department or study site; 1st grade relatives, or partners of the investigator, or patients who are dependent on the sponsor
23. Any physical or mental condition that precludes administration of allergen-specific immunotherapy, compliance or participation in a trial
24. Patients who are placed in an institution due to governmental or judicial directive

E.5 End points

E.5.1

Primary end point(s)

Safety and tolerability of different dosages of SUBLIVAC FIX Mite mixture compared to placebo assessed by number and severity of local and systemic reactions.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 1month of treatment.

E.5.2

Secondary end point(s)

Safety of different dosages of SUBLIVAC FIX Mite mixture compared to placebo assessed by number and severity of AEs
• Safety of different dosages of SUBLIVAC FIX Mite mixture compared to placebo assessed by clinical and laboratory parameters
• Changes in serum specific immunoglobulin levels (IgE, IgG, IgG4) after 1 month of treatment with different dosages of SUBLIVAC FIX Mite mixture compared to placebo
• Proportions of patients in the different treatment groups reaching maintenance dose within 10 days

E.5.2.1

Timepoint(s) of evaluation of this end point

After 1 month 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

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

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

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

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:

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

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)

The sponsor does not continue to follow the subjects after the end of the trial: though the investigator may independently follow-up with the subjects based on local practice standards.

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

2015-01-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-11-19

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