Clinical Trials Register

Summary
EudraCT Number:	2022-000215-31
Sponsor's Protocol Code Number:	S65796
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-04-05
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2022-000215-31

A.3

Full title of the trial

A monocentric academic trial comparing the diagnostic value of history taking and nasal lysine aspirin provocation test in the diagnosis of AERD in CRSwNP patients

A.3.1

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

Value of nasal provocation test with aspirin in the diagnosis of AERD in patients with chronic sinusitis with nasal polyps

A.4.1

Sponsor's protocol code number

S65796

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	UZ Leuven
B.1.3.4	Country	Belgium
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	The Research Foundation – Flanders (FWO)
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UZ Leuven
B.5.2	Functional name of contact point	Otorhinolaryngology, head and neck
B.5.3	Address:
B.5.3.1	Street Address	Herestraat 49
B.5.3.2	Town/ city	Leuven
B.5.3.3	Post code	3000
B.5.3.4	Country	Belgium
B.5.6	E-mail	nkogh_info@uzleuven.be

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	Aspegic 500 mg - Powder for oral solution
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Belgium
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Powder for oral solution in sachet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Nasal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	D,L-Lysine Acetylsalicylate
D.3.9.1	CAS number	62952-06-1
D.3.9.3	Other descriptive name	LYSINE ASPIRIN
D.3.9.4	EV Substance Code	SUB34053
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	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.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	Yes
D.2.1.1.1	Trade name	Mini-Plasco NaCl B.Braun - Solution for injection - 0,9%
D.2.1.1.2	Name of the Marketing Authorisation holder	B. Braun Melsungen AG
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Nasal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Sodium chloride
D.3.9.1	CAS number	7647-14-5
D.3.9.3	Other descriptive name	NaCl
D.3.9.4	EV Substance Code	SUB12581MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/V) percent weight/volume
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.9
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	Nasal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Aspirin-Exacerbated Respiratory Disease (AERD) in patients with Chronic RhinoSinusitis with Nasal Polyps (CRSwNP)

E.1.1.1

Medical condition in easily understood language

Patients with chronic rhinosinusitis with nasal polyps, suffering from Aspirin Induced Asthma (AIA)

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	25.1
E.1.2	Level	LLT
E.1.2	Classification code	10075084
E.1.2	Term	Aspirin-exacerbated respiratory disease
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

This clinical trial aims to determine the diagnostic performance and safety of nasal LAS provocation testing in the ENT department of a Belgian hospital to diagnose AERD in CRSwNP patients. Therefore, the trial has the following objectives:
Primary objectives: (1) To determine the diagnostic performance by assessing the degree of agreement between history taking and the nasal provocation test for the diagnosis of AERD within CRSwNP patients and within different subgroups of CRSwNP patients defined by the severity of their condition (NPS, SNOT-22, ACQ-6, VAS, FEV1, PNIF)
(2) To evaluate the safety of the procedure in terms of: (a) use of rescue medication other than nasal decongestants and short-acting beta2-agonists; (b) unplanned health care resource utilization; (c) allergic reactions not resolved after an observation period of 2 hours.

E.2.2

Secondary objectives of the trial

Secondary objectives: Optimizing the procedure: To evaluate the step doses: if the percentage of participants with positive reactions on a certain provocative dose is strongly higher and the gap between the previous dose too much, than a lower dose could had been given with more safety for the patient
Exploratory objectives: (1) To assess the effect of LAS on bronchial and nasal inflammation, (2) To assess the effect of LAS on exploratory biomarkers of inflammation, (3) To investigate biomarkers for predicting response to LAS, (4) To identify differences in upper airway inflammatory signature between CRSwNP and AERD, (5) To determine whether endotypic subtypes of AERD may exist.
Furthermore, this trial will precede a main trial in which the capability of nasal ATAD to ameliorate AERD in CRSwNP will be tested. Therefore, the challenge test will serve as first step towards desensitization for the patients who tested positive.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients older than 18 years and younger than 75 years.
- Patients with CRSwNP: (1) Presence of two or more symptoms for 12 weeks, one of which should be either nasal blockage/ obstruction/ congestion or nasal discharge (anterior/ posterior nasal drip) AND (2) Endoscopic signs of nasal polyps (bilateral) or history of revision sinus surgery in the treatment of bilateral nasal polyps.
- Control cases: Patients with allergic rhinitis (AR): Presence of two or more symptoms for > 1 hour on most days: watery anterior rhinorrhoea /sneezing, especially paroxysmal/ nasal obstruction /nasal pruritis. AR must be confirmed by IgE test in blood and/or on skin.
- Control cases: healthy volunteers: participants without clinical or radiographic history of sinus disease and with no known typical coexisting type 2 inflammatory diseases of nasal polyp disease, defined as asthma, allergic rhinitis, atopic dermatitis/eczema, urticaria, food allergy or eosinophilic esophagitis (based on anamnesis).

E.4

Principal exclusion criteria

- Participant has a history of anaphylaxis or of urticaria/angioedema to aspirin/NSAID. Participant had a reaction to aspirin/NSAID occurring within 10 minutes as this is likely to be IgE-mediated.
- Female who is pregnant, breast-feeding or is of child-bearing potential and not using an adequate, highly effective contraceptive.
- Participants with chronic urticaria, unstable cardiovascular conditions or severe or unstable/brittle asthma (FEV1 < 65% on preventative inhalers).
- Participants who have taken biologic therapy within 3 months prior to screening or 5 half-lives, whichever is longer.
- Participants who have undergone any intranasal and/or sinus surgery (including polypectomy) within 3 months before screening.
- Participants experiencing an asthma exacerbation requiring hospitalization (>24 hours) for treatment of asthma within 3 months before screening.
- Initiation of allergen immunotherapy within 3 months prior to screening or a plan to begin therapy or change its dose during the screening period.
- Participants with major anatomical nasal abnormalities or conditions/concomitant diseases being responsible for nasal obstruction and making them nonevaluable at screening or for the nasal provocation test including, but not limited to: antrochoanal polyps, nasal septal deviation that would occlude at least one nostril, acute sinusitis, nasal infection or upper respiratory infection within 4 weeks prior to the test requiring treatment with systemic antibiotics, antivirals or antifungals.
- Participants not willing to respect the wash-out period or not willing to take the necessary precautions in preparation to the challenge test as defined in section 5.3 ‘Concomitant/Prohibited Medication/Treatment

E.5 End points

E.5.1

Primary end point(s)

Diagnostic performance:
- The proportion of patients scoring positive for AERD according to the challenge test
- The proportion of patients scoring positive for AERD according to the questionnaire
- Level of IgE, count of eosinophils, NPS, SNOT-22 score and ACQ-6 score at baseline
- Change from baseline in score on VAS for nasal-and chest symptoms, PNIF value and FEV1 value
Safety:
- The proportion of patients requiring other rescue medication than nasal decongestants and short-acting beta2-agonists, per class of drugs
- The number of emergency room visits and urgent care interventions
- The proportion of patients with allergic reactions not resolved after an observation period of 2 hours

E.5.1.1

Timepoint(s) of evaluation of this end point

at the end of the trial

E.5.2

Secondary end point(s)

Optimizing the procedure:
- Incidence of positive reactions on the nasal provocation test per provocative dose
Exploratory:
- Change from baseline in the concentration of exhaled and nasal NO
- Change from baseline in biomarkers of inflammation (cytokines representative of type 1, 2 and 3 inflammation and arachidonic acid derived lipid mediators) in nasal secretion and mucous membrane

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the trial

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

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

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

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

control group: patients without the disease

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

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)

F.1.2.1

Number of subjects for this age range:

176

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

Yes

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

236

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)

As AERD is under-diagnosed and outcomes are worse in these patients, it is important to identify the hypersensitivity. Patients who proved positive on the nasal LAS challenge test will be warned about avoidance of NSAIDs, including aspirin, and offered the option of nasal LAS desensitization in a follow-up study if all the inclusion criteria are met. Participation will be on voluntary basis.

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

2022-04-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-05-24

P. End of Trial
P.	End of Trial Status	Ongoing

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