Clinical Trials Register

Summary
EudraCT Number:	2019-003775-19
Sponsor's Protocol Code Number:	EFC16461
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:	2020-02-04
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

2019-003775-19

A.3

Full title of the trial

Master protocol of three randomized, double-blind, placebo-controlled, multi center, parallel-group studies of dupilumab in patients with chronic spontaneous urticaria (CSU) who remain symptomatic despite the use of H1 antihistamine treatment in patients naïve to omalizumab and in patients who are intolerant or incomplete responders to omalizumab

A.3.1

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

Dupilumab for the treatment of chronic spontaneous urticaria in patients who remain symptomatic despite the use of H1 antihistamine and who are naïve to, intolerant of, or incomplete responders to omalizumab.

A.3.2

Name or abbreviated title of the trial where available

CUPID

A.4.1

Sponsor's protocol code number

EFC16461

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	Sanofi-Aventis Recherche & Développement
B.1.3.4	Country	France
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	Sanofi-aventis Recherche & Développement
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sanofi-Aventis Deutschland GmbH
B.5.2	Functional name of contact point
B.5.3.4	Country	Germany
B.5.6	E-mail	medinfo.de@sanofi.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	Dupilumab
D.3.2	Product code	SAR231893
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
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	Dupilumab
D.3.9.2	Current sponsor code	SAR231893
D.3.9.3	Other descriptive name	REGN668
D.3.9.4	EV Substance Code	SUB88511
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
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)	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	Yes
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	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	Dupilumab
D.3.2	Product code	SAR231893
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
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	Dupilumab
D.3.9.2	Current sponsor code	SAR231893
D.3.9.3	Other descriptive name	REGN668
D.3.9.4	EV Substance Code	SUB88511
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	175
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)	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	Yes
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 in pre-filled syringe
D.8.4	Route of administration of the placebo	Subcutaneous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection in pre-filled syringe
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

Chronic spontaneous urticaria

E.1.1.1

Medical condition in easily understood language

Chronic spontaneous urticaria

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10072757
E.1.2	Term	Chronic spontaneous urticaria
E.1.2	System Organ Class	10040785 - Skin and subcutaneous tissue 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 the efficacy of dupilumab in study participants with CSU who remain symptomatic despite the use of H1 antihistamine (Study A and Study C: omalizumab naïve; Study B: omalizumab intolerant or incomplete responders)

E.2.2

Secondary objectives of the trial

- To demonstrate the efficacy of dupilumab on urticaria activity composite endpoint and itch or hives, separately, at various timepoints
- To demonstrate the efficacy of dupilumab on angioedema
- To demonstrate the efficacy of dupilumab on urticaria control
- To demonstrate improvement in health-related quality of life and overall disease status and severity
- To evaluate the ability of dupilumab in reducing the proportion of patients who require treatment with oral corticosteroids (OCS)
- To evaluate safety outcome measures
- To evaluate immunogenicity of dupilumab

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Study A and C: Participant must be ≥6 years to 80 years of age at the time of signing the informed consent.
- Study B: Participant must be ≥12 years (or the minimum legal age for adolescents in the country of the investigational site) to 80 years of age at the time of signing the informed consent
- Participants who have a diagnosis of CSU refractory to H1 antihistamines (H1-AH) at the time of randomization defined by
• Diagnosis of CSU>6 months prior to screening visit
• Presence of itch and hives for >6 consecutive weeks at any time prior to screening visit despite the use of H1-AH during this time period
• Using a study defined H1-antihistamine for CSU treatment
• During the 7 days before randomization:
UAS7=>16
ISS7=> 8
• In-clinic UAS> 4 prior to randomization
- Study A and C: omalizumab naïve, Study B; intolerant or incomplete responder to omalizumab
- Participants must be willing and able to complete a daily symptom eDiary for the duration of the study

E.4

Principal exclusion criteria

Participants are excluded from any of the studies if any of the following criteria apply:
- Weight is less than 30 kg in adults and adolescents and 15 kg in children aged 6 to<12years
- Clearly defined underlying etiology for chronic urticarias other than CSU
- Presence of skin morbidities other than CSU that may interfere with the assessment of the study outcomes
- Active atopic dermatitis
- Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect the patient’s participation in the study
- Active tuberculosis or non-tuberculous mycobacterial infection, or a history of incompletely treated tuberculosis
- Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic infection
- Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before the screening visit and during the screening period
- Known or suspected immunodeficiency
- Active malignancy or history of malignancy within 5 years before the baseline visit, except completely treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin.
- History of systemic hypersensitivity or anaphylaxis to omalizumab or any biologic therapy, including any excipients

E.5 End points

E.5.1

Primary end point(s)

1 - Change from baseline in weekly itch severity score (except EU and EU reference countries) ; Change from baseline in weekly itch severity score (ISS7) at Week 24
2 - For EU and EU reference countries only: change from baseline in weekly urticaria activity score ; Change from baseline in weekly urticaria activity score (UAS7, composite patient reported itch and hive score) at Week 24

E.5.1.1

Timepoint(s) of evaluation of this end point

1, 2 - Baseline to Week 24

E.5.2

Secondary end point(s)

1 - Change from baseline in weekly urticaria activity score (UAS7, composite patient reported itch and hive score) at Week 12 and Week 24 (except EU and EU reference countries)
2 - Change from baseline in ISS7 at Week 12 and Week 24 (in EU and EU reference countries)
3 - Time to ISS7 minimally important (MID) (ISS7 ≥5) response ; The itch severity score will be recorded daily in the patient eDiary, on a scale of 0 (none) to 3 (severe).The weekly itch score is the sum of the daily itch scores over 7 days
4 - Proportion of ISS7 MID (≥5 points) responders at Week 12 and Week 24 ; The itch severity score will be recorded daily in the patient eDiary, on a scale of 0 (none) to 3 (severe).The weekly itch score is the sum of the daily itch scores over 7 days.
5 - Change from baseline in ISS7 at all time points (onset of action is assessed by the first p<0.05 that remains significant at subsequent measures until Week 24 ; The itch severity score will be recorded daily in the patient eDiary, on a scale of 0 (none) to 3 (severe).The weekly itch score is the sum of the daily itch scores over 7 days
6 - Change from baseline in UAS7 at Week 12 ; The UAS is a composite eDiary-recorded score with numeric severity intensity ratings on a scale of 0-3 (0=none to 3=intense/severe) for 1) the number of wheals (hives); and 2) the intensity of the itch measured daily. UAS7 is the sum of the daily UAS scores over 7 days.
7 - 8 - Proportion of patients with UAS7 ≤6 at Week 12 and Week 24 / Proportion of patients with UAS7=0 at Week 12 and Week 24 ; The UAS is a composite eDiary-recorded score with numeric severity intensity ratings on a scale of 0-3 (0=none to 3=intense/severe) for 1) the number of wheals (hives); and 2) the intensity of the itch measured daily. UAS7 is the sum of the daily UAS scores over 7 days.
9 - Change from baseline in angioedema activity score over 7 days (AAS7) at Week 12 and Week 24 ; Angioedema activity score (AAS) is recorded once daily in the Diary by the participants. This validated tool assesses episodes of angioedema including their duration, severity and impact on daily functioning and appearance.
10 - Change from baseline in urticaria control test (UCT) at Week 12 and Week 24 ; The urticarial control test (UCT) is instrument that works in all types of chronic urticaria (not only for CSU), and it can also be used in urticaria patients suffering from recurrent angioedema.otal score ranges 0 to 16; higher scores indicate better disease control.
11 - Proportion of well controlled patients (UCT ≥12) at Week 12 and Week 24 ; The urticarial control test (UCT) is instrument that works in all types of chronic urticaria (not only for CSU), and it can also be used in urticaria patients suffering from recurrent angioedema.otal score ranges 0 to 16; higher scores indicate better disease control. Scores ≥12 are consistent with well-controlled disease.
12 - Change from baseline in health-related quality-of-life ; Change from baseline in health-related quality-of-life (HRQoL) as measured by Dermatology Life Quality Index (DLQI) in patients ≥16 years old, and in Children’s Dermatology Life Quality Index (CDLQI) in patients ≥6 - <16 years old at Week 12 and Week 24
13 - Change from baseline in Patient Global Impression of Severity (PGIS) of CSU at Week 12 and Week 24; The Patient Global Impression of Severity (PGIS◦) is a one-item questionnaire that asks participants to provide the overall self-assessment of their participant’ disease severity on a 4-point scale for the past week.
14 - Patient Global Assessment of Change (PGIC) of CSU at Week 12 and Week 24; The Patient Global Impression of Change (PGIC) is a one-item questionnaire that asks the participant to provide the overall self-assessment of change in their CSU on a 7-point scale, compared to just before participant started taking the study treatment
15 - Proportion and time to event of patients receiving OCS for CSU during the planned treatment period ;
16 - Safety; Percentage of participants experiencing treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs)
Immunogenicity; Incidence of treatment-emergent ADA against dupilumab over time

E.5.2.1

Timepoint(s) of evaluation of this end point

1, 2 : Baseline to Week 12 and Week 24
3 : Baseline over time until Week 24
4 : Week 12 and Week 24
5 : Baseline to Week 24
6 : Baseline to Week 12
7, 8 : Week 12 and Week 24
9, 10 : Baseline to Week 12 and Week 24
11 : Week 12 and Week 24
12, 13 : Baseline to Week 12 and Week 24
14 : Week 12 and Week 24
15 : Baseline over time to Week 24
16 : Baseline to Week 24

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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

Information not present in EudraCT

E.8.4

The trial involves multiple sites in the Member State concerned

Information not present in EudraCT

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Canada

China

Japan

Russian Federation

United Kingdom

United States

France

Germany

Hungary

Spain

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

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:

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:

420

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

101

F.4.2.2

In the whole clinical trial

521

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

2020-02-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-09-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-10-25

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