Clinical Trials Register

Summary
EudraCT Number:	2020-005135-73
Sponsor's Protocol Code Number:	DC05DUO/2/20
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2022-03-02
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

Bulgarian Drug Agency

A.2

EudraCT number

2020-005135-73

A.3

Full title of the trial

A Randomised, Double-blind, Two-arm, Parallel Groups, Multicentre Study to evaluate the efficacy and safety of a Fixed Dose Combination of Rupatadine and Montelukast vs. Rupatadine in adult patients with Seasonal Allergic Rhinitis with and without mild to moderate Bronchial Asthma

Рандомизирано, двойно сляпо, с две рамена, паралелно-групово, многоцентрово проучване за оценка на ефикасността и безопасността на комбинация с фиксирана доза на рупатадин и монтелукаст спрямо рупатадин при възрастни пациенти със сезонен алергичен ринит с и без лека до умерена степен на бронхиална астма

A.3.1

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

A clinical trial to evaluate the safety and the efficacy of a combination of Rupatadine and Montelukast compared to Rupatadine in patients with Allergic Rhinitis

Клинично изпитване за оценка на безопасността и ефикасността на комбинация от Rupatadine и Montelukast в сравнение с Rupatadine при пациенти с алергичен ринит.

A.3.2

Name or abbreviated title of the trial where available

DREAM-SAR

A.4.1

Sponsor's protocol code number

DC05DUO/2/20

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	Biohorm, S.L.
B.1.3.4	Country	Spain
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	Biohorm, S.L.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Biohorm, S.L.
B.5.2	Functional name of contact point	Daniel Peris
B.5.3	Address:
B.5.3.1	Street Address	Av. Camí Reial, 51-57
B.5.3.2	Town/ city	Palau-solità i Plegamans
B.5.3.3	Post code	08184
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3493 737 66 90
B.5.5	Fax number	+3493 864 66 06
B.5.6	E-mail	daniel.peris@noucor.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	Yes
D.2.1.1.1	Trade name	Rupafin 10 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Noucor Health, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Rupatadine
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RUPATADINE
D.3.9.1	CAS number	158876-82-5
D.3.9.4	EV Substance Code	SUB10406MIG
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	10
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	SINGULAIR 10 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SHARP & DOHME DE ESPAÑA, S.A
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Montelukast
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Montelukast
D.3.9.1	CAS number	151767-02-1
D.3.9.3	Other descriptive name	MONTELUKAST
D.3.9.4	EV Substance Code	SUB09054MIG
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	10
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	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Seasonal allergic rhinitis with and without mild to moderate bronchial asthma

E.1.1.1

Medical condition in easily understood language

Seasonal alergic rhinitis with or without asthma

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10001723
E.1.2	Term	Allergic rhinitis
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

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 demonstrate therapeutic superiority of the test FDC product (rupatadine and motelukast) over rupatadine monotherapy in seasonal allergic rhinitis patients with and without mild to moderate bronchial asthma inadequately controlled.

E.2.2

Secondary objectives of the trial

To assess efficacy and safety parameters of the fix dose combination and to collect additional data that supports superiority in terms of efficacy versus monotherapy with rupatadine

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent in accordance with applicable regulatory requirements.
2. Male and female outpatients aged 18 or more with at least 1-year history of SAR inadequately controlled and in need of alternative treatments as per the treating physicians with or without mild to moderate allergic bronchial asthma.
3. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use methods of contraception (barrier methods and oral contraceptives) throughout the study visits.
4. Positive skin prick test (wheal +/- 3 mm larger than the diluent control) to at least one seasonal allergen specific to their geographical location.
5. Evaluation of four nasal symptoms scores (T4NSS) measured as a reflective way (12 hours apart in the morning and evening periods) at screening.
6. Adequate wash-out to baseline if patients are taking any of the medications mentioned in table below. Nasal corticosteroids are the unique medication allowed in this period.
Additional inclusion criteria for patients with asthma
1. History of asthma for at least 6 months before screening.
2. Adult patients with mild-to-moderate asthma partially controlled by beclomethasone dipropionate ≤500 μg/d or equivalent according to GINA guidelines as shown in the table below (alone or in combination with long term β2-adrenergic bronchodilators).

E.4

Principal exclusion criteria

1. Active acute or chronic pulmonary disorder, acute sinus disease that have not resolved within 1 week (active hay fever and AR symptoms are allowed), and upper respiratory tract infection within 3 weeks, emergency department treatment of asthma within 1 month, and hospitalization for asthma within 3 months before the randomization visit.
2. Bronchial asthma patients who receive treatment with inhaled corticosteroids (ICS), alone or in combination with short and/or long term β2-adrenergic bronchodilators, at dosage >500 μg beclomethasone dipropionate or equivalent (budesonide >400 μg/d, ciclesonide >160 μg/d, fluticasone >250 μg/d and mometasone >400 μg/d) within 2 weeks.
3. Daily treatment with montelukast within 7 days prior to randomization, cetirizine and bilastine (3 days), levocetirizine (2 days), loratadine, desloratadine, rupatadine and any other oral H1 antihistaminic not listed above (6 days), systemic corticosteroids (28 days), ketotifen (2 weeks), macrolides and imidazolic antifungals (7 days), anticholinergic drugs (7 days), topical antihistaminic drugs (e.g. nasal or drops) (2 days), drugs with antihistamine properties (e. g. phenothiazine) (6 days), intranasal/systemic decongestants and eye drops (3 days).
4. Patients suffering from non-allergic rhinitis (e.g., vasomotor, infectious, or drug-induced rhinitis).
5. Patients who had undergone nasal surgery in the previous 6 months and patients with nasal polyps, significant deviation of the nasal septum, acute or chronic sinusitis.
6. Clinically relevant respiratory tract malformations.
7. Recent nasal biopsy (within 2 months).
8. Nasal trauma; nasal surgery; atrophic rhinitis; rhinitis medicamentosa (within 2 months).
9. Antibiotic use for acute conditions within 2 weeks of screening.
10. History of QT prolongation and/or torsade de pointes, including congenital long QT syndromes, history of cardiac arrhythmias.
11. Smokers who report consuming more than 10 cigarettes per day.
12. History or presence of an immunodeficiency disorder.
13. Hypersensitivity to any beta-agonist, sympathomimetic drug, leukotriene antagonist.
14. Patients with a known history of HIV, hepatitis B or hepatitis C infection.
15. Any abnormal laboratory value of clinical relevance.
16. Pregnant or nursing mother.
17. Current evidence of any clinically significant disease of the hematopoietic, gastrointestinal, cardiovascular, pulmonary, or any other systems that might hinder the subject participation.
18. Abuse or dependency of alcohol, narcotics, opioids or any other addictive substances.
19. Patients that participated in any type of clinical study within the last month of the screening date.
20. Unsuitability for enrollment otherwise as decided by the investigator.
21. The drug products contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take these drugs.
22. Patients who had received immunotherapy for less than 6 months (unless on a stable dose within the prior month, and none within 24 hours before any study visit) or any Central Nervous System (CNS) acting agents (including antidepressants, sedatives, anxiolytics, hypnotics, opioids or neuroleptics) at any time.

E.5 End points

E.5.1

Primary end point(s)

The main efficacy endpoint will be the change in the T4NSS on the 28 day of treatment (PDC reflective 12 hours symptoms, every day including the visit days with the investigator) compared with Day 0.

E.5.1.1

Timepoint(s) of evaluation of this end point

End of treatment (day 28±2)

E.5.2

Secondary end point(s)

• Change in the total score of patient symptoms (T7SS) on the 28 day of treatment (reflective evaluation) compared with Day 0.
• Change in the total score of non-nasal patient symptoms (T3NNSS) on the 28 day of treatment (reflective evaluation) compared with Day 0.
• Change in the daily score for each symptom (DSS) on the 28 day of treatment (reflective evaluation) compared with Day 0.
• Mean value of the daily total score of symptoms (mTSS).
• Time to beginning of action (first week).
• Percentage of patients requiring rescue medication.
• Assessment of instantaneous overall effectiveness (both patient and investigator)
• Improvement in quality of life (Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ]) evaluated.

E.5.2.1

Timepoint(s) of evaluation of this end point

End of treatment (day 28±2)

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)

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

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

Last Patient Last 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

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:

290

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

130

F.4.2

For a multinational trial

F.4.2.1

In the EEA

300

F.4.2.2

In the whole clinical trial

300

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 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

2022-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-05-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-09-15

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