Clinical Trials Register

Summary
EudraCT Number:	2016-000051-27
Sponsor's Protocol Code Number:	PM/0041
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-06-08
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

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2016-000051-27

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled (DBPC) parallel-group multi-centre study to assess the efficacy and safety of PURETHAL Mites subcutaneous immunotherapy (SCIT) in patients with allergic rhinitis/rhinoconjunctivitis (ARC) caused by house dust mite (HDM) allergy

Randomizované, dvojito zaslepené, placebom kontrolované multicentrické skúšanie vykonávané v paralelných skupinách na hodnotenie účinnosti a bezpečnosti lieku PURETHAL Mites podávaného subkutánne v rámci imunoterapie pacientom s alergickou rinitídou/rinokonjunktivitídou spôsobenou alergiou na roztoče v domácom prachu (HDM)

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

PURETHAL Mites pivotal phIII efficacy study

A.4.1

Sponsor's protocol code number

PM/0041

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 Manager
B.5.3	Address:
B.5.3.1	Street Address	J.H. Oortweg 15
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	+31881959 185
B.5.5	Fax number	+31881959 001
B.5.6	E-mail	emantikou@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	PURETHAL® Mites
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	A modified house dust mite extract from Dermatophagoides pteronyssinus and Dermatophagoides farinae
D.3.9.1	CAS number	8000045-20-7
D.3.9.3	Other descriptive name	ALLERGENS, HOUSE DUST & MITE
D.3.9.4	EV Substance Code	SUB12784MIG
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 AUeq/ml
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	Yes
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 rhinitis/rhinoconjunctivitis (ARC) caused by house dust mite (HDM) allergy.

E.1.1.1

Medical condition in easily understood language

House dust mite (HDM) allergy.

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

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	10001724
E.1.2	Term	Allergic rhinitis (excl hay fever)
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

To assess clinical efficacy of 50,000 AUeq/mL (0.5 mL) PM SCIT, compared to placebo, in patients suffering from HDM-induced ARC, measured by the combined symptom and medication score (CSMS(n)) during the last 8 weeks of approximately 1 year treatment. For this primary CSMS(n) evaluation, the symptom score of the CSMS(n) will be based on nasal symptoms only.

E.2.2

Secondary objectives of the trial

• To assess clinical efficacy of PM, compared to placebo, measured by the:
o dSS(n) (mean individual daily symptom scores, nasal symptoms only) assessed during the last 8 weeks of the approximately 1 year treatment period;
o dMS (mean daily medication score) assessed during the last 8 weeks of the approximately 1 year treatment period;
o Difference in NPT (nasal provocation test) at the end of study compared to baseline.
• To determine the onset of efficacy based on CSMS(n) for PM vs placebo.
• To compare the proportion of ‘symptom-free days’ (i.e. days without nasal symptoms) and ‘troubled days’ (i.e. days with CSMS(n) ≥ 1.5), assessed during the last 8 weeks of the approximately 1 year treatment period.
• To assess the effect of PM, compared to placebo, on Quality of Life (QoL) after approximately 1 year of treatment.
• To assess the effect of PM, compared to placebo, on serum specific immunoglobulin levels.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients who signed their informed consent form.
2. Patients aged ≥18 and ≤65 years at signing of informed consent form.
3. Patients with moderate to severe HDM-induced allergic rhinitis or rhinoconjunctivitis (based on ARIA classification) for at least one year prior to screening; with or without concomitant asthma (asthma must be controlled (GINA 2010)).
4. Patients with a history of concomitant asthma must have an FEV1 >70% of predicted value, at screening. Patients without a history of asthma must have an FEV1 >70% or a PEF >80% of predicted value at screening.
5. Patient that reported a mean CSMS(n) ≥1.5 during the baseline period .
6. Patients that are willing and capable to complete an e-diary daily during 12 weeks of the study (≥60% compliance in e-diary completion during the 14 days baseline period).
7. Patients with a positive SPT for HDM D. pter or D. far (mean wheal diameter ≥3 mm compared to negative control; for negative control a reaction up to 2 mm is allowed; histamine control should be positive (mean wheal diameter ≥3 mm) assessed during screening or a documented positive response obtained within one year before screening.
8. Patients with an allergen specific serum IgE (ssIgE) level for HDM D. pter or D. far of ≥0.7 U/mL assessed during screening.
9. Patients with a positive NPT for HDM D. pter extract during screening (Lebel score ≥6 at 10,000 AU/mL), test should be postponed if baseline score is ≥ 3 or if negative control is >3.

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)) to other allergens than HDM, if they have expected clinically relevant symptoms related to the other allergen, overlapping with either the 8-week efficacy assessment period and/or the screening/baseline period, based on the judgement of the investigator.
2. Patients sensitized and symptomatic to pets, that will be regularly exposed to pets during the study period.
3. Patients with a history of anaphylaxis with cardio-respiratory symptoms (food allergy, drugs or an idiopathic reaction).
4. Patients who received immunotherapy (SCIT or SLIT) with HDM allergens within the past 5 years.
5. Patients with unsuccessful allergen-specific immunotherapy (SCIT or SLIT) within the past 5 years (e.g., but not limited to, prematurely stopped immunotherapy due to non-compliance, AEs, or lack of therapeutic effect).
6. Patients who undergo allergen-specific immunotherapy (SCIT or SLIT) with other allergens than HDM during the study period (screening up to EoS).
7. Patients who participated in a clinical study within the last 3 months (e.g. new investigational drug or biological) or within the last 30 days (e.g. observational study), or in an observational study within the last 30 days (e.g. post marketing study),or plans on participating in another clinical trial during the duration of this study, at the discretion of the investigator.
8. Patients that (will) receive any vaccination (including influenza vaccine) one week before start of treatment and/or during the up-dosing phase.
9. Patients undergoing any immunosuppressive treatment (e.g. anti-IgE therapy) within the last 6 months prior to inclusion and up to EoS.
10. Patients suffering from severe immune disorders (including auto-immune diseases) and/or diseases requiring immunosuppressive drugs.
11. Patients suffering from active malignancies or any malignant disease during 5 years prior to screening.
12. Patients suffering from any 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: clinically significant abnormal ECG at screening or cardiovascular insufficiency, any severe or unstable lung diseases, endocrine disorders, clinically significant renal or hepatic diseases, haematological disorders, severe atopic dermatitis.
13. Patients suffering from any disease with a contra-indication for the use of epinephrine/adrenaline (e.g. hyperthyroidism, glaucoma).
14. Patients receiving treatment with systemic corticosteroids 4 weeks before screening, nasal corticosteroids 2 weeks before the screening, antihistamines 3 days before screening during the indicated timeframe as listed in Table 4.
15. Patients receiving treatment with systemic or local beta-blockers (including beta-blocker containing eye drops) any time during the study.
16. Patients suffering from moderate to severe nasal obstructive disease such as polyps, septum deviations, etc.
17. Patients suffering from clinically significant chronic sinusitis or ocular infection.
18. Female patients of child-bearing potential who are pregnant, lactating or using inadequate contraceptive measures.
Contraceptive measures considered adequate are:
1) hormonal contraceptives such as contraceptive pills, transdermal patches, intrauterine device (IUD), intrauterine system (IUS) implant, or vaginal ring (started at least 4 weeks prior to IMP administration);
2) double barrier methods: e.g. condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent;
3) surgical female participant sterilization (removal of the uterus or ovaries or tubal ligation (”tied tubes”));
4) postmenopausal (12 consecutive months without a period) for at least 2 years;
5) male partner sterilization (vasectomy with documentation of azoospermia) prior to the female patient's entry into trial and is the sole sexual partner for that female patient;
6) sexual abstinence or having no sexual relationship with a man.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the Combined Symptom (nasal symptoms only) and Medication Score CSMS(n).
The primary evaluation of the CSMS(n) includes only nasal symptoms; itchy nose, sneezing, runny nose, and blocked nose (all rated from 0-3), and the medication score; 1 for oral and/or topical antihistamines, 2 for intranasal corticosteroids, and 3 for oral corticosteroids. The eye symptoms will not be taken into account in the primary evaluation, because these are less relevant for HDM induced allergies (23). The scores from the four nasal symptoms are added and divided by 4 to a total daily symptom score (dSS(n)) from 0-3. The medication score can reach a maximum of 3 and the total daily medication score ranges from 0-3. The CSMS(n) will range from 0-6.

The EAACI has recently published a position paper on the use of the CSMS as a primary end-point in allergen immunotherapy trials.

Baseline CSMS(n) will be determined during a period of 14 days during the screening period . After randomization, the e-diary will be filled out during two separate periods of 1 week (this will be skipped for patients that are suffering from any co-allergy during these periods), and during the last part of the study patients will be asked to fill in the symptom and medication e-diary on a daily basis for a period of 8 weeks. Timing of this 8 weeks period depends on the randomization date of the patients. For details on the timing of this efficacy period, please refer to the SoE (Table 1). Scores for each of these periods will be averaged. The mean CSMS(n) is the mean of the non-missing daily scores during the period considered. Patients will be asked to fill in their CSMS(n) daily on a fixed time window. For the primary endpoint the data collected during the last 8 weeks of the approximately 1 year treatment period will be used.

E.5.1.1

Timepoint(s) of evaluation of this end point

Difference in mean CSMS(n) (nasal symptoms only) between PM vs. placebo treatment group, will be assessed during the last 8 weeks of the approximately 1 year treatment period.

E.5.2

Secondary end point(s)

Efficacy
• dSS(n) (nasal symptoms only), measured during the last 8 weeks of the approximately 1 year
treatment period.
• dMS measured during the last 8 weeks of the approximately 1 year treatment period.
• Difference in change from baseline in NPT outcome (Lebel score).
• Onset of efficacy based on CSMS(n), measured during the two one-week periods during treatment
and during the last 8 weeks of the approximately 1 year treatment period.
• Proportion of ‘symptom-free days’ (i.e. days without nasal symptoms) and ‘troubled days’ (i.e. days
with CSMS(n) ≥ 1.5), assessed during the last 8 weeks of the approximately 1 year treatment period.
• QoL measured with the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ-S) and
EQ-5D-5L questionnaire, for all patients; and an additional asthma control questionnaire (ACQ, for
patients with concomitant asthma only) as measured at the end of treatment.
• Difference from baseline in serum specific immunoglobulin levels (IgE, IgG, IgG4) between PM and
placebo, during and after treatment.

Safety
• Safety and tolerability assessed by:
o local and systemic reactions
o (serious) adverse events
o blood safety biochemistry/haematology parameters (including aluminium content)
o urinalysis (including aluminium content)
o vital signs
o ECG
in PM compared to placebo, as measured before, during and after treatment.

Exploratory
• Difference in CSMS (nasal and conjunctival symptoms) between PM and placebo, measured during
the last 8 weeks of the approximately 1 year treatment period.
• dSS (nasal and conjunctival symptoms), measured during the last 8 weeks of the approximately 1
year treatment period.
• Difference in QoL measured with the standardized rhinoconjunctivitis quality of life questionnaire
(RQLQ-S) and EQ-5D-5L questionnaire, for all patients; and an additional asthma control
questionnaire (ACQ, for patients with concomitant asthma only) as measured two time points during
treatment.
• Difference in mean CSMS(n) between PM and placebo with sufficient HDM exposure at the
patients’ home measured both at screening and at the end of the study.
• Clinical efficacy of PM, compared to placebo, on asthma parameters (e.g. asthma related concomitant medication, asthma related adverse events and lung function)

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

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

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:

730

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

730

F.4.2.2

In the whole clinical trial

730

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)

If allowed following local country regulations, patients will receive PM (20,000 AUeq/mL) as post-study medication after completion of the study. Patients that received placebo during the study will receive 3 years, patients that received active will receive 2 years of PM therapy as post study medication.

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

2016-08-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-04-23

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