Clinical Trials Register

Summary
EudraCT Number:	2018-001339-33
Sponsor's Protocol Code Number:	SCITVITD3
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-06-07
Trial 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

Netherlands - Competent Authority

A.2

EudraCT number

2018-001339-33

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, study to determine the added value of vitamin D3 to treatment with subcutaneous immunotherapy in patients with moderate to severe allergic rhinitis/ rhinoconjunctivitis caused by birch pollen

A.3.1

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

A study to determine the added value of vitamin D3 to treatment with subcutaneous immunotherapy in patients with birch pollen allergy

A.3.2

Name or abbreviated title of the trial where available

SCITVITD3

A.4.1

Sponsor's protocol code number

SCITVITD3

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	Academisch medisch centrum Amsterdam
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Academisch medisch centrum Amsterdam
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	Academisch medisch centrum Amsterdam
B.5.2	Functional name of contact point	Clinical trial Information
B.5.3	Address:
B.5.3.1	Street Address	Meibergdreef 9
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1105AZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+310205666819
B.5.6	E-mail	l.zuidmeer@amc.uva.nl

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	Yes
D.2.1.1.1	Trade name	Zemplar
D.2.1.1.2	Name of the Marketing Authorisation holder	AbbVie Ltd
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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)	No
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	Solution 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

subcutaneous immunotherapy in allergic rhinitis (AR) patients with allergies to birchpollen

E.1.1.1

Medical condition in easily understood language

allergic rhinitis patients with allergies to birchpollen

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

MedDRA Classification

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 primary objective is the assessment of serological and cellular immunological changes and kinetics thereof induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen in a pre-seasonal short-term course of SCIT.
To this end, the primary outcome of the study is the IL-10 production by PBMCs in response to allergen-specific stimulation after 5 weeks of treatment with VD3 analogue Zemplar® compared to placebo (visit 7).

E.2.2

Secondary objectives of the trial

Differences in the following parameters will be measured after (5 and) 11 weeks of treatment with SCIT +/- VD3:

• The IL-10 production by PBMCs in response to allergen-specific or polyclonal stimulation.
• Cellular composition of PBMC (Th1,2,17,22, Tregs, B cells, and APCs.
• PBMC proliferatiskinon and cytokine production in response to allergen or polyclonal stimuli.
• Intracellular cytokines in response to PMA/ionomycin.
• IgE, IgG and IgG4 responses in serum to birchpollen and Bet v 1.
• The functional blocking antibody capacity of IgG/IgG4.
• Titrated SPT with birchpollen extract as a surrogate clinical marker of efficacy.
• Monitoring of epigenetic changes.
• Identification of predictive and efficacy-associated biomarkers by transcriptomics on nasal brushing.
• Clinical efficacy by titrated nasal provocation test, peak nasal inspiratory flow, the combined symptom medication score (CSMS) and an electronic diary (e-diary).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent
2. Age ≥18 ≤ 65 years
3. Moderate to severe birch-pollen-induced AR/ARC of at least 2 years according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines (Appendix 1, see manual) with or without concomitant mild to moderate persistent asthma
4. FEV1>70% for patients with a history of asthma, FEV1>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 birch pollen assessed within 1 year before randomization
6. A positive ImmunoCAP (>0.7 kU/L) for birch pollen
7. A positive tNPT (for rules when a tNPT is positive see ref 40a)

E.4

Principal exclusion criteria

1. Clinically relevant co-sensitization (others than hazel, alder and elm) expected during the birch-pollen season.
2. Chronic asthma with an FEV1<70 % of predicted value.
3. History of AIT (SCIT or SLIT) with any allergen within the past 5 years
4. Ongoing AIT (SCIT or SLIT) with any allergen(s) during the study period
5. Current Treatment with VD3 analogue.
6. Vaccination within one week before or during the treatment phase.
7. Immunosuppressive or biological medication (e.g. IL-5, anti-IgE therapy) within the last six months prior to inclusion and up to end of trial (EoT).
8. Severe immune disorders (including auto-immune diseases) and/or diseases requiring immunosuppressive drugs.
9. Uncontrolled asthma or other active respiratory diseases.
10. Active malignancies or any malignant disease during the previous 5 years.
11. 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.
12. Active inflammation or infection of the target organs (nose, eyes or lower airways) at the start of the study.
13. Moderate to severe nasal obstructive diseases that preclude a TNPT (e.g., septal deviation, nasal polyps) or nasal/sinus surgery in the last 3 months.
14. Diseases with a contraindication for the use of adrenaline (e.g. hyperthyroidism, glaucoma).
15. Use of systemic steroids within 4 weeks before start of the study and during the study.
16. Treatment with systemic and local β-blockers.
17. Pregnancy, lactation or inadequate contraceptive measures for women of child-bearing age (adequate contraceptive measures will be the use of a contraceptive device or oral contraceptive pill).
18. Alcohol, drug or medication abuse within the past year.
19. Any clinically significant abnormal laboratory parameter at screening.
20. Lack of cooperation or compliance.
21. Any physical or mental condition that precludes administration of SCIT, compliance or participation in a clinical trial.
22. Patients who are students or employees of the institution or 1st grade relatives or partners of the investigators
23. Participation in a clinical trial within 3 months prior to the current trial.

E.5 End points

E.5.1

Primary end point(s)

The primary outcome of the study is the IL-10 production by PBMCs in response to allergen-specific stimulation after 5 weeks of treatment with VD3 analogue Zemplar® compared to placebo.

E.5.1.1

Timepoint(s) of evaluation of this end point

5 weeks of treatment

E.5.2

Secondary end point(s)

• The IL-10 production by PBMCs in response to allergen-specific stimulation after 11 weeks of treatment with VD3 analogue Zemplar® compared to placebo.
• The IL-10 production by PBMCs in response to polyclonal stimulation after 5 and 11 weeks of treatment with VD3 analogue Zemplar® compared to placebo.
• Determination of the difference between cellular composition of PBMC with respect to Th1, Th2, Th17, Th22, and Treg cells, B cells, and antigen-presenting cells (APC) induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.
• Determination of the difference between PBMC proliferation and cytokine production in response to allergen (Bet v 1) induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.
• Determination of the difference between PBMC proliferation and cytokine production in response to polyclonal stimuli (αCD3/αCD28) induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.
• Determination of the difference between intracellular cytokine measurements in response to PMA/ionomycin induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.
• Determination of the changes in IgE, IgG and IgG4 antibody responses in serum to birch pollen and Bet v 1 induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.
• Determination of changes in a so-called IgE facilitated allergen-binding assay (FAB) and in a rat basophilic leukemia cell (RBL)-based histamine release test after 5 and 11 weeks of treatment, to monitor the functional blocking antibody capacity of induced IgG/IgG4 antibodies.
• Evaluation of changes in a titrated skin prick test (SPT) with birch pollen extract after 5 and 11 weeks of treatment, as a surrogate clinical marker of efficacy.
• Monitoring of epigenetic changes after 5 and 11 weeks of treatment.
• The identification of predictive and efficacy-associated biomarkers by transcriptomics on nasal brushing taken at after 5 and 11 weeks of treatment.
• Determination of a difference in clinical efficacy of SCIT with VD3 compared to SCIT alone, as analysed for the upper airways by titrated nasal provocation test (TNPT), including an objective read-out i.e. peak nasal inspiratory flow (PNIF), after 5 and 11 weeks of treatment.
• Determination of a difference in clinical efficacy of SCIT with VD3 compared to SCIT alone, assessed by monitoring symptoms and medication in the birch pollen season with the combined symptom medication score (CSMS) of EAACI and the use of an electronic diary (e-diary). In a subset of patients with allergic asthma, asthma control will be evaluated during birch pollen season.

E.5.2.1

Timepoint(s) of evaluation of this end point

5 and 11 weeks 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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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)

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

2018-06-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-07-15

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