Clinical Trials Register

Summary
EudraCT Number:	2021-002317-34
Sponsor's Protocol Code Number:	AL2101av
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:	2021-11-19
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

2021-002317-34

A.3

Full title of the trial

A multicenter, randomized, open label clinical trial for safety evaluation of an allergen immunotherapy with an accelerated dose escalation schedule using one strength of an aluminium hydroxide adsorbed allergoid preparation of birch pollen allergens in adult and pediatric patients with moderate to severe seasonal allergic rhinitis or rhinoconjunctivitis with or without bronchial asthma.

Eine multizentrische, randomisierte, offene Klinische Prüfung zur Untersuchung der Verträglichkeit eines verkürzten Aufdosierungsschemas für ein Einstärken-Präparat zur spezifischen Immuntherapie mit einem Aluminiumhydroxid adsorbierten Allergoid aus Birkenpollenallergenen bei Erwachsenen, Jugendlichen und Kindern mit mittelschwerer bis schwerer allergischer Rhinitis oder Rhinokonjunktivits mit oder ohne Asthma.

A.3.1

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

Study to investigate the safety of an accelarated (fast) dose escalation schedule using one strength birch pollen allergens as compared to the approved long (slow) two-dose escalation in adult and pediatric patients with allergic cold (with and w/o asthma).

Studie zur Untersuchung der Sicherheit eines beschleunigten (schnellen) Dosiseskalationsschemas unter Verwendung von Birkenpollenallergenen in einer Stärke im Vergleich zu der zugelassenen langen (langsamen) Dosiseskalation mit zwei Dosen bei erwachsenen und minderjährigen Patienten mit allergischem Schnupfen (mit und ohne Asthma).

A.3.2

Name or abbreviated title of the trial where available

ONSeT Birch (One strength Birch)

A.4.1

Sponsor's protocol code number

AL2101av

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	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 Development
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	+494072765614
B.5.5	Fax number	+494072765600
B.5.6	E-mail	Christiane.Praechter@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	Allergovit Birch
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.3.9.3	Other descriptive name	WHITE BIRCH POLLEN ALLERGOID FORMALDEHYDE MODIFIED
D.3.9.4	EV Substance Code	SUB74925
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000
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	Comparator
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	ALLERGOVIT® Birch
D.2.1.1.2	Name of the Marketing Authorisation holder	Allergopharma GmbH & Co. KG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Allergovit Birch
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.3.9.3	Other descriptive name	WHITE BIRCH POLLEN ALLERGOID FORMALDEHYDE MODIFIED
D.3.9.4	EV Substance Code	SUB74925
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1000 to 10000
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

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 seasonal allergic rhinitis or rhinoconjunctivitis with or w/o asthma caused by birch pollen allergens

E.1.1.1

Medical condition in easily understood language

moderate to severe seasonal allergic cold with or w/o asthma caused by birch pollen

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

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	10001726
E.1.2	Term	Allergic rhinitis due to pollen
E.1.2	System Organ Class	100000004870

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	10001728
E.1.2	Term	Allergic rhinoconjunctivitis
E.1.2	System Organ Class	100000004853

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 evaluate the safety and tolerability of a One strength dose escalation scheme using One strength of Allergovit Birch for allergen immunotherapy (AIT) compared to the standard escalation scheme using 2 strength of Allergovit Birch in adults, adolescents, and children with allergic rhinitis/rhinoconjunctivitis caused by birch pollen allergens with or without allergic asthma on a well-controlled level

E.2.2

Secondary objectives of the trial

not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent given from patient and if relevant parents/legal guardian(s) according to local requirements before any trial-related activities started (a trial-related activity is any procedure that would not have been performed during routine management of the patient)

2. Age between 5 and ≤ 65 years

3. IgE-mediated moderate to severe allergic rhinitis or rhinoconjunctivitis with or without allergic asthma caused by sensitization to birch pollen allergens documented by:
• Positive Skin prick test (SPT) result to birch pollen allergens:
- Birch pollen test solution (wheal diameter) ≥ 3 mm and
- Positive histamine-control reaction (wheal diameter) ≥ 3 mm and
- Negative NaCl 0.9%-control reaction (wheal diameter) < 2 mm
• Moderate to severe rhinitis acc. to ARIA guideline (Brozek et al. 2017, Bousquet et al. 2001)
• Immunoassay result for specific IgE ≥ 0.70 kU/L to birch pollen allergens

4. Symptoms of allergic rhinitis or rhinoconjunctivitis from March to May on birch pollen exposure during the last 2 seasons

5. At entry to this trial: no diagnosis of bronchial asthma in medical history or confirmed diagnosis of asthma which is “well controlled” according to GINA recommendation (GINA 2021)

6. Previous symptomatic anti-allergic treatment for at least 2 seasons prior to enrolment

7. Negative SARS-CoV-2 test result (PCR or antigen test) during the screening period

E.4

Principal exclusion criteria

General criteria:
1. Patients and, if relevant parents/legal guardian(s), are unable to understand and comply with the requirements of the trial, as judged by the investigator
2. Currently participation in another clinical trial or participation in any other clinical trial within 30 days prior to informed consent for this trial
3. Low adherence to trial procedures expected or inability to understand instructions/trial documents by participant and/or parents/legal guardian(s)
4. Involvement in the planning and conduct of the trial
5. Patients and, if relevant parents/legal guardian(s) is/are employee(s) of Allergopharma GmbH & Co. KG or of one of the trial sites or CRO
6. Any relationship of dependence with the sponsor or with the investigator(s)
7. Previous randomization to treatment in the present trial
8. Mentally disabled
9. Institutionalized due to an official or judicial order

For female patients with childbearing potential
10. Positive urine pregnancy test or pregnant
11. Wish to become pregnant during the course of the trial
12. Not using highly effective and reliable contraception, as judged by the investigator (reliable and highly effective methods of birth control defined as failure rate of less
than 1% per year)
13. Wish to breast feed or breast feeding

Immunotherapy criteria:
14. History of a confirmed anaphylaxis after an AIT injection
15. AIT with birch pollen allergoids or allergens within the last 5 years
16. Current treatment with any kind of allergen immunotherapy (AIT)
17. AIT with unknown allergen within the last 5 years

Diseases and health status:
18. Clinically relevant chronic rhinoconjunctival or respiratory symptoms related to other reasons than allergy
19. Forced expiratory volume in 1 second (FEV1) < 70 % of predicted normal values according to Quanjer et al. (2012) under adequate asthma treatment according to GINA recommendation (GINA 2021)
20. Uncontrolled or partly controlled asthma according to GINA recommendation
(GINA 2021)
21. Asthma exacerbation within the last 6 months prior to randomization defined as unscheduled doctors visit, hospitalization, or emergency unit visit requiring the use
of systemic corticosteroid or change in controller medication
22. Severe acute or chronic diseases (e.g. COVID-19, chronic urticaria, mastocytosis, active tuberculosis, diabetes mellitus type I, malignant neoplasia, chronic renal failure), severe inflammatory diseases (liver, kidneys), acute viral and bacterial infections presenting with fever
23. Autoimmune diseases, immune defects including immunosuppression, immune-complex-induced immunopathies (e.g. HIV, post-transplant patients, lupus erythematodes [SLE], vitiligo, Grave’s disease, multiple sclerosis)
24. Severe psychiatric and psychological disorders including impairment of cooperation (e.g. alcohol or drug abuse)
25. Recurrent seizures (e.g. febrile convulsion, untreated epilepsy)
26. Irreversible secondary alterations of the reactive organ (e.g. emphysema, bronchiectasis)
27. For assessment the normal reference ranges of the central laboratory should be applied If out of range, laboratory values greater than grade 1 according to the FDA Guidance for Industry (Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials) will lead to exclusion of the patients (Generally, this applies to patients of all age groups in this trial). However, for laboratory values with ages specific reference ranges of the central laboratory and when these normal reference ranges partly overlap with the toxicity grading scale, e.g. hemoglobin in children and young adolescents, medical judgement should be applied for in- and exclusion of the individual paediatric patient. Moreover, the values regarding esoinophils will be accepted also above the normal ranges because these values are considered as allergy marker.

Medication:
28. Use of β-blockers (locally or systemically), and/or ACE inhibitors
29. Contraindication for use of adrenalin (e.g. acute or chronic symptomatic coronary heart disease, severe hypertension)
30. Completion or ongoing treatment with anti-IgE-antibodies (e.g. omalizumab) or anti-
IL-4/IL-5 receptor-antibodies (e.g. dupilumab) or other biological medication interfering with the T2 pathway)
31. Hypersensitivity to excipients of the investigational medical product Allergovit Birch

E.5 End points

E.5.1

Primary end point(s)

descriptive safety variables
1) Number, incidence, time of onset, type and intensity of AEs and serious adverse events (SAE) according to MedDRA primary system organ class (SOC) and preferred term
2) Number, incidence, time of onset, type and intensity of AEs and serious adverse events assessed as IMP-related (by investigator) according to MedDRA primary SOC and preferred term
3) Incidence and intensity of allergic systemic reactions after injections according to the World Allergy Organization (WAO) grading system
4) Number of patients reaching the maintenance dose without dose adjustment due to adverse events
5) Change of laboratory values (hematology, clinical chemistry and urinalysis) measured before and after the treatment phase
6) Change of vital signs and lung function measured before and after the treatment phase
7) Assessment of the overall tolerability at study end by the investigator and the patient using a 5 point Likert scale (Likert 1932)

E.5.1.1

Timepoint(s) of evaluation of this end point

Endpoints 1 - 3 will be evaluated using cumulative data from every visit (except screening visit).

Endpoint 4 will be evaluated at week 2 (Group I, One Strength) / at week 6 (Group II, Standard).

Endpoints 5 and 6 will be evaluated at Screening (before IMP-injection) and Final Visit (14-28 days after last IMP-injection).

Endpoint 7 will be evaluated retrospectively before the next injection, starting at Treatment-Visit 2 through the final visit.

E.5.2

Secondary end point(s)

exploratory endpoint:
•Serum specific IgG4 to Betula verrucosa pollen allergen extract

E.5.2.1

Timepoint(s) of evaluation of this end point

The exploratory endpoint will be evaluated at Screening and Final Visit.

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

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

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

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:

140

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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

210

F.4.2.2

In the whole clinical trial

210

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)

None

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

2021-11-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-03-29

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