Clinical Trials Register

Summary
EudraCT Number:	2015-000188-15
Sponsor's Protocol Code Number:	AL1402ac
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:	2016-11-03
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

2015-000188-15

A.3

Full title of the trial

A multicenter randomized double-blind placebo-controlled clinical trial for evaluation of efficacy and safety of specific immunotherapy with an aluminium hydroxide-adsorbed allergoid preparation of house dust mite
(Dermatophagoides pteronyssinus) in patients with allergic bronchial asthma and with allergic rhinitis or rhinoconjunctivitis

Multizentrische, randomisierte, doppelblinde, Placebo-kontrollierte klinische Studie zur Beurteilung der Wirksamkeit und Sicherheit der spezifischen Immuntherapie mit einem an Aluminiumhydroxid adsorbierten Allergoidpräparat von Hausstaubmilben (Dermatophagoides pteronyssinus) bei Patienten mit allergischem Asthma bronchiale und mit allergischer Rhinitis oder Rhinokonjunktivitis

A.3.1

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

Phase III trial of specific immunotherapy with allergoid preparation of house dust mite in patients with allergic bronchial asthma and with allergic rhinitis or rhinoconjunctivitis

Phase III-Studie der spezifischen Immuntherapie mit einem Allergoidpräparat von Hausstaubmilben bei Patienten mit allergischem Asthma bronchiale und mit allergischer Rhinitis oder Rhinokonjunktivitis

A.4.1

Sponsor's protocol code number

AL1402ac

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/286/2010

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Allergopharma GmbH & Co. KG
B.1.3.4	Country	Germany
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	Allergopharma GmbH & Co. KG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Allergopharma GmbH & Co. KG
B.5.2	Functional name of contact point	Clinical Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Hermann-Körner-Straße 52
B.5.3.2	Town/ city	Reinbek
B.5.3.3	Post code	21465
B.5.3.4	Country	Germany
B.5.4	Telephone number	+494027 65 - 0
B.5.5	Fax number	+4940727 65 – 600
B.5.6	E-mail	AL1402ac@allergopharma.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	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	N/A
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.9.3	Other descriptive name	DERMATOPHAGOIDES PTERONYSSINUS
D.3.9.4	EV Substance Code	SUB25740
D.3.10	Strength
D.3.10.1	Concentration unit	PNU/ml protein nitrogen units/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	900
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	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	N/A
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.9.3	Other descriptive name	DERMATOPHAGOIDES PTERONYSSINUS
D.3.9.4	EV Substance Code	SUB25740
D.3.10	Strength
D.3.10.1	Concentration unit	PNU/ml protein nitrogen units/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	9000
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	Suspension for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

allergic bronchial asthma and allergic rhinitis or rhinoconjunctivitis

E.1.1.1

Medical condition in easily understood language

asthma with symptoms of rhinitis or rhinoconjunctivitis caused by house dust mite allergens

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10039097
E.1.2	Term	Rhinoconjunctivitis
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10001705
E.1.2	Term	Allergic asthma
E.1.2	System Organ Class	100000004855

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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

The aim of this clinical trial is to demonstrate efficacy and to evaluate safety of AIT with an aluminium hydroxide adsorbed allergoid preparation of major allergens of D p in patients with allergic bronchial asthma (acc. to GINA 2016) and allergic rhinitis or rhinoconjunctivitis caused by house dust mites.

E.2.2

Secondary objectives of the trial

None

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent and assent according to local requirements before any trial-related activities started (a trial-related activity is any procedure that would not have been performed during the routine management of the patient.)
2. Male or female outpatient between 12 and 65 years (both inclusive),
but Italy and Russia: 18 - 65 years only
3. IgE-mediated allergic bronchial asthma treated according GINA step 2-4 with rhinitis or rhinoconjunctivitis induced by house dust mite documented by
• SPT wheal for D p ≥ 3 mm in diameter
• histamine (0.1% histamine) wheal ≥ 3 mm
• a negative control reaction (NaCl) wheal < 2 mm
• Immunoassay result specific IgE > 1.5 kU/L to D p
• symptoms of asthma and rhinitis or rhinoconjunctivitis e.g. during the months September to February or over the entire year
4. confirmed diagnosis of asthma
• treatment according to GINA 2016 during the last year as documented by requirement of ICS and in addition, either the requirement of a long acting bronchodilator or as needed of a short-acting bronchodilator
• FEV1 increase of ≥ 12% and 200 mL of the baseline FEV1 after inhalation of 400µg of Salbutamol or other short acting bronchodilator equivalent (historical data not older than 2 years are acceptable). A methacholine test (≥ 20% FEV1 decrease after Methacholine provocation test) in the historical data is acceptable)
• Achievement of asthma control criteria (ACQ6 ≤ 1.0 scores in 2 consecutive weeks at the end of the assessment period) during the baseline diary phase within a required ICS dose between 400 to 1200 µg Budesonide per day

E.4

Principal exclusion criteria

General criteria:
1. Unable to understand and comply with the requirements of the trial, as judged by the investigator
2. Currently participating in any other trial or in participating in any other trial within 30 days before inclusion in this trial
3. Low compliance, persistent incorrect inhaler technique as assessed by the investigator or inability to understand instructions or trial documents
4. Involved in the planning and conduct of the trial
5. Employee of Allergopharma GmbH & Co. KG or of one of the trial sites
6. Any relationship of dependence with the sponsor or with the investigator
7. Previously enrolled or randomized to treatment in the present trial
8. Mentally disabled
9. Institutionalized due to an official or judicial order
For females with childbearing potential (i.e. females who are not chemically or surgically sterilized or females who are not post-menopausal [defined as 12 months with no menses without an alternative medical cause]):
10. Positive pregnancy test
11. Use of an unacceptable or unreliable contraceptive method during the trial as judged by the investigator (reliable and highly effective methods of birth control defined as failure rate less than 1% per year [CTFG recommendations 15 Sep 2014]). Sexual abstinence is an allowed method of birth control (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.)
Males are not required to use any contraception during the study.
12. Pregnant, breast feeding or wishes to breast feed
13. Seeking to become pregnant during the course of the trial
Immunotherapy criteria:
14. Any AIT with house dust mites
15. Current treatment with any kind of immunotherapy
16. Any AIT with unknown allergen
17. Clinically relevant symptoms to perennial and seasonal allergens which interfere with the assessment period of October to January. Exceptions are symptoms to allergens of cat and dog, if the patient has no direct contact to these animals.
18. Sensitization in the immunoassay ≥ 0.7 kU/L against perennial and seasonal allergens which interfere with the assessment period of October to January. Exceptions are sensitizations to storage mites if the sensitization assessed by immunoassay is lower than the sensitization to at least one of the house dust mites (D p or D f). Exceptions are sensitizations assessed by immunoassay to cat and dog, if the patient has no direct contact to these animals.
Diseases and health status:
19. Clinically relevant rhinitis or respiratory symptoms related to other reasons (e.g. chronic sinusitis, COPD)
20. FEV1 < 70% of predicted normal (ECSC) at best asthma control status
21. Chronic, persistent asthma or rhinitis symptoms for 20 years or longer
22. Laboratory values greater than Grade 1 (for hematological values Grade 2) according to the FDA Guidance for Industry (Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials). For assessment the normal ranges of the central laboratory will be applied.
23. Severe acute or chronic diseases (e.g. Diabetes mellitus type I, malignant neoplasia, chronic renal failure, gastro-esophageal reflux disease, BMI > 30, aspirin induced asthma, active tuberculosis), severe inflammatory diseases (liver, kidneys)
24. Autoimmune diseases, immune-defects including immune-suppression, immune-complex-induced immunopathies (e.g. HIV, post-transplant patients, lupus erythematodes (SLE), Grave’s disease)
25. Severe psychiatric and psychological disorders including impairment of cooperation (e.g. alcohol or drug abuse)
26. Current Smoker or use of e-cigarettes
27. Ex-smoker with 10 pack years or more (A pack year is defined as twenty cigarettes smoked every day for one year)
28. Recurrent seizures
29. Irreversible secondary alterations of the reactive organ (e.g. emphysema, bronchiectasis etc.)

Medications:
30. Treatment with beta-blockers (local or systemic)
31. Contraindication for use of adrenalin (e.g. acute or chronic symptomatic coronary heart disease, severe hypertension)
32. Completed or ongoing treatment with anti-IgE-antibody
33. Completed or ongoing long-term treatment with tranquilizer or other psychoactive drugs
34. Controlled asthma at baseline after 2 steps of ICS reduction

E.5 End points

E.5.1

Primary end point(s)

This is a confirmatory phase III pivotal study. The primary endpoint is the change in dose steps of the minimum daily ICS dose required to ensure asthma control (well controlled and partly controlled) according to the ACQ6 (ACQ6 score ≤ 1.0) between baseline and after AIT. The ICS dose will be determined by means of diary entries as described in Section 5.1.

E.5.1.1

Timepoint(s) of evaluation of this end point

after the end of the trial

E.5.2

Secondary end point(s)

The following secondary endpoints will be assessed:
Efficacy
“Change” refers to the change between the baseline value and the value after AIT.
• Response status in terms of improvement by at least one dose step of the minimum daily ICS dose required to ensure asthma control between baseline and after AIT
• Response status in terms of no need for ICS after AIT
• Change of the minimum daily ICS dose (Budesonide) in µg required to ensure asthma control.
• Change in ACQ6 score under the highest daily ICS dose the patient was not controlled at baseline according to the ACQ6.
• Change in severity of asthma symptoms with the highest daily ICS dose the patient was not controlled at baseline
• Change in use of bronchodilator rescue medication (Salbutamol) with the daily ICS highest dose the patient was not controlled at baseline
• Change in pre-bronchodilator morning peak flow with the highest daily ICS dose the patient was not controlled at baseline
• Change in the number of night time awakening with the highest daily ICS dose the patient was not controlled at baseline
• Change in limitation of daily activities with the highest daily ICS dose the patient was not controlled at baseline
• Change in the number of symptom free days with the highest daily ICS dose the patient was not controlled at baseline
• Change in the outcome of the Quality of Life Questionnaire (Mini-AQLQ*) with the highest daily ICS dose the patient was not controlled at baseline
• Change in patient’s FEV1 value with the highest daily dose ICS the patient was not controlled at baseline
• Change of the Combined Symptom (rhinitis symptoms) and Medication Score (CSMS) under the lowest daily ICS dose required to ensure asthma control at baseline
• Change of the Combined Symptom (rhinitis- and conjunctivitis symptoms) and Medication Score (CSMS) under the lowest daily ICS dose required to ensure asthma control at baseline
• Change of rhinitis symptoms of the CSMS under the lowest daily ICS dose required to ensure asthma control at baseline
• Change of the rhinitis medication score of the CSMS under the lowest daily ICS dose required to ensure asthma control at baseline
• Change of IgG4
• Change of eosinophils
• The time until the first moderate or severe asthma exacerbation during the diary phase after AIT
• The time until the first moderate or severe asthma exacerbation from the time of first injection until the end of trial.
• The number of asthma exacerbations (moderate or severe) during the diary phase after AIT.
• The number of asthma exacerbations (moderate or severe) from the time of first injection until the end of trial.
• Number of severe asthma exacerbations during the diary phase after AIT
The number of severe asthma exacerbations from the time of first injection until the end of trial.
• Number of moderate asthma exacerbations during the diary phase after AIT
• The number of moderate asthma exacerbations from the time of first injection until the end of trial.
Safety
In addition to the efficacy endpoints, the safety of the treatment during the entire trial period will be assessed by
• Adverse events
• Clinical laboratory tests (hematology, clinical chemistry, and urinalysis)
• Vital signs (resting blood pressure, pulse rate, and respiratory rate)
• An assessment of the overall tolerability by the investigator and the patient using a 5 point Likert scale (Likert, 1932)

*MiniAQLQ is not available in Croatia and Romania

E.5.2.1

Timepoint(s) of evaluation of this end point

After the end of the trial

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Croatia

Germany

Italy

Latvia

Lithuania

Poland

Romania

Russian Federation

Serbia

Spain

Ukraine

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

The end of the trial is defined as the date of last database lock in order to permit data cleaning after the last patient visit.

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

Yes

F.1.1

Number of subjects for this age range:

133

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

133

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

313

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.4.2

For a multinational trial

F.4.2.1

In the EEA

336

F.4.2.2

In the whole clinical trial

446

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)

Standard of medical care

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

2017-04-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-06-25

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