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Clinical Trial Results:
A multicenter, randomized, double-blind, placebo-controlled, phase 2, 16-week treatment study with a 16 week follow-up period to assess the efficacy and safety of Dupilumab (anti-IL4Ra) in adult patients with chronic spontaneous urticaria despite H1-antihistamine treatment.

Summary
EudraCT number	2017-004458-41
Trial protocol	DE
Global end of trial date	01 Oct 2021

Results information
Results version number	v1(current)
This version publication date	19 May 2023
First version publication date	19 May 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

D-001-01

ISRCTN number

US NCT number

NCT03749135

WHO universal trial number (UTN)

Sponsor organisation name

Charité - Universitätsmedizin Berlin

Sponsor organisation address

Charitéplatz 1, Berlin, Germany, 10117

Public contact

Prof. Marcus Maurer , Charité - Universitätsmedizin Berlin, Institute of Allergology, Hindenburgdamm 30, 12203 Berlin, marcus.maurer@charite.de

Scientific contact

Prof. Marcus Maurer , Charité - Universitätsmedizin Berlin, Institute of Allergology, Hindenburgdamm 30, 12203 Berlin, marcus.maurer@charite.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Feb 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

07 Jul 2021

Global end of trial reached?

Yes

Global end of trial date

01 Oct 2021

Was the trial ended prematurely?

Main objective of the trial

The primary objective is the evaluation of Dupilumab (600 mg loading dose and subsequent 300 mg regular long term dose) being superior to placebo regarding be the difference in the change in urticaria activity score 7 (UAS7) from baseline to week 16 in adult patients with moderate to severe CSU and with H1-antihistamine resistant alone or in combination with LTRA.

Protection of trial subjects

Safety assessment included adverse event reporting and routine clinical and laboratory assessments. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Dupilumab is a human monoclonal antibody that inhibits IL-4 and IL-13 signaling by binding to the IL-4Rα. Dupilumab was previously found to be effective in atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, prurigo nodularis, and eosinophilic esophagitis. Considering that CSU and atopic diseases share many common features (e.g. key pathogenic role of mast cells and IgE, itch is a dominant symptom, Th2 dominance), it was reasonable to expect that Dupilumab is beneficial in CSU.

Evidence for comparator

Actual start date of recruitment

04 Oct 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 73

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 6 study centers in Germany, between 04/10/2018 and 07/07/2021.

Screening details

92 patients were assessed for eligibility, 73 patients were randomised. All patients included in this study will be subjected at the screening visit, V0 (day -14) to physical examination, vital signs & weight assessment, electrocardiogram, serum pregnancy test and basic laboratory control (hematology panel, clinical chemistry panel, urinalysis).

Period 1 title

Study Drug Period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Are arms mutually exclusive

Yes

Dupilumab

Arm description

Patients received Dupilumab 600 mg (2 injections) initially, followed by Dupilumab 300 mg (1 injection) administered subcutaneously every two weeks.

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

SAR231893

Other name

Dupixent

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Dupilumab 600 mg s.c. loading dose followed by 300 mg every two weeks

Placebo

Arm description

patients received two injections placebo (2 injections of 2 ml) on randomization visit and afterwards one injection every two weeks (injections of 2 mL).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Placebo

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo s.c. loading dose followed by Placebo injection s.c. biweekly for 14 weeks

Number of subjects in period 1	Dupilumab	Placebo
Started	48	25
Completed	36	22
Not completed	12	3
Consent withdrawn by subject	7	2
Adverse event, non-fatal	1	-
Pregnancy	-	1
Lost to follow-up	4	-

Baseline characteristics

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Reporting group title

Dupilumab

Reporting group description

Patients received Dupilumab 600 mg (2 injections) initially, followed by Dupilumab 300 mg (1 injection) administered subcutaneously every two weeks.

Reporting group title

Placebo

Reporting group description

patients received two injections placebo (2 injections of 2 ml) on randomization visit and afterwards one injection every two weeks (injections of 2 mL).

Reporting group values	Dupilumab	Placebo	Total
Number of subjects	48	25	73
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	46	20	66
From 65-84 years	2	5	7
85 years and over	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	40 ± 14.5	45.3 ± 6.3	-
Gender categorical
Units: Subjects
Female	28	16	44
Male	20	9	29
Skin type (Fitzpatrick)
Units: Subjects
Typ I	1	1	2
Typ II	36	17	53
Typ III	10	5	15
Typ IV	1	2	3
IgE subgroups
Units: Subjects
<100 kU/l	21	15	36
≥100 kU/l	27	10	37
UAS7 subgroups
Units: Subjects
UAS7 < 28	27	10	37
UAS7 ≥ 28	21	15	36
CSU duration
Units: Subjects
>10 years	16	10	26
2-10 years	27	9	36
<2 years	5	6	11
Total IgE
Units: IU/ml
arithmetic mean (standard deviation)	199.2 ± 223.8	90.6 ± 70.6	-
UAS7 score
urticaria activity score 7, UAS7, also used clinically, is the sum of UAS scores over 7 consecutive days.
Units: Score
arithmetic mean (standard deviation)	25.9 ± 7.9	26.8 ± 8.9	-
HSS7 score
The weekly Hives Severity Score
Units: Score
arithmetic mean (standard deviation)	12.6 ± 5.2	13.3 ± 5.1	-
ISS7 score
Weekly Itch Severity Score (ISS7)
Units: Score
arithmetic mean (standard deviation)	13.4 ± 4.2	13.5 ± 4.7	-
AAS7
Weekly Angioedema Activity Score (AAS7)
Units: Score
arithmetic mean (standard deviation)	33.5 ± 22.1	32.3 ± 19.0	-
UCT
Urticaria Control Test
Units: Score
arithmetic mean (standard deviation)	5.3 ± 2.9	4.9 ± 3.2	-
DLQI
The Dermatology life Quality Index (DLQI) is a ten-question questionnaire used to measure the impact of skin disease on the quality of life of an affected person. It is designed for people aged 16 years and abov
Units: score
arithmetic mean (standard deviation)	11.4 ± 6.5	12.4 ± 7.6	-
CU-Q2oL
Chronic Urticaria Quality of Life questionnaire (CU-Q2oL)
Units: Score
arithmetic mean (standard deviation)	44.1 ± 17.7	45.1 ± 16.5	-

End points

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Reporting group title

Dupilumab

Reporting group description

Patients received Dupilumab 600 mg (2 injections) initially, followed by Dupilumab 300 mg (1 injection) administered subcutaneously every two weeks.

Reporting group title

Placebo

Reporting group description

patients received two injections placebo (2 injections of 2 ml) on randomization visit and afterwards one injection every two weeks (injections of 2 mL).

Primary: change in urticaria activity score 7 (UAS7)

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End point title

change in urticaria activity score 7 (UAS7)

End point description

The primary analysis of the primary endpoint (change of the UAS7 from baseline to week 16, with lower values indicating an improvement) was performed on the ITT-population comparing treatments (Dupilumab vs. placebo) in an analysis of covariance (ANCOVA) model with the fixed factors treatment and study sites (sites with 10 or less patients were pooled together for this analysis), and with baseline UAS7 score (visit 1) as a covariate. The adjusted (least square, LS) group means for each treatment group was presented with their respective 95% confidence interval and an exploratory p-value for the group difference. The primary endpoint was tested for treatment differences using the non-parametric Wilcoxon Rank Sum Test and with an (unadjusted) analysis of variance (ANOVA) model as sensitivity analyses. In addition, the primary analysis was repeated for the per-protocol-population and for the full analysis set (FAS).

End point type

Primary

End point timeframe

from baseline to week 16

End point values	Dupilumab	Placebo
Number of subjects analysed	36	22
Units: score
median (inter-quartile range (Q1-Q3))	16.0 (8.5 to 25.0)	15.0 (1.0 to 28.0)

Attachments

results_secondary-endpoints

change in UAS7 from baseline to week 16

Statistical analysis description

The secondary analysis of the primary outcome was performed for treatment differences using the non-parametric Wilcoxon Rank Sum Test (Table 5-6) and with an (unadjusted) analysis of variance (ANOVA) model (Table 5-7) as sensitivity analyses.

Comparison groups

Dupilumab v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.307

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-3.1

Confidence interval

level

95%

sides

2-sided

lower limit

-9.2

upper limit

Variability estimate

Standard error of the mean

Dispersion value

3.04

Notes
[1] - The primary analysis of the primary endpoint (change of the UAS7 from baseline to week 16, with lower values indicating an improvement) was performed on the ITT-population comparing treatments (Dupilumab vs. placebo) in an analysis of covariance (ANCOVA) model with the fixed factors treatment and study sites (sites with 10 or less patients were pooled together for this analysis), and with baseline UAS7 score (visit 1) as a covariate. The adjusted (least square, LS) group means for each treatment

Adverse events

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Timeframe for reporting adverse events

overall time

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Dupilumab

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Dupilumab	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 48 (4.17%)	1 / 25 (4.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
General disorders and administration site conditions
Cellulitis right upper arm at site of reaction, hospit.
subjects affected / exposed	1 / 48 (2.08%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
servere urticaria with hospitalisation
subjects affected / exposed	0 / 48 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 48 (2.08%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Dupilumab	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	38 / 48 (79.17%)	20 / 25 (80.00%)
Nervous system disorders
Headache
subjects affected / exposed	6 / 48 (12.50%)	3 / 25 (12.00%)
occurrences all number	10	5
General disorders and administration site conditions
Reaction at injection side/local site reaction
subjects affected / exposed	3 / 48 (6.25%)	1 / 25 (4.00%)
occurrences all number	12	1
Fever
subjects affected / exposed	2 / 48 (4.17%)	0 / 25 (0.00%)
occurrences all number	3	0
Nausea and Vomitting
subjects affected / exposed	4 / 48 (8.33%)	1 / 25 (4.00%)
occurrences all number	7	2
Fatigue
subjects affected / exposed	1 / 48 (2.08%)	3 / 25 (12.00%)
occurrences all number	1	3
Immune system disorders
Insect sting with swelling/hurting
subjects affected / exposed	6 / 48 (12.50%)	1 / 25 (4.00%)
occurrences all number	6	1
Eye disorders
Dry eyes
subjects affected / exposed	3 / 48 (6.25%)	1 / 25 (4.00%)
occurrences all number	3	1
Gastrointestinal disorders
Gastritis, Stomach pain
subjects affected / exposed	2 / 48 (4.17%)	2 / 25 (8.00%)
occurrences all number	2	3
Diarrhea, Adominal pain
subjects affected / exposed	5 / 48 (10.42%)	5 / 25 (20.00%)
occurrences all number	5	5
Respiratory, thoracic and mediastinal disorders
Sore throat
subjects affected / exposed	0 / 48 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	3
Skin and subcutaneous tissue disorders
Scabies
subjects affected / exposed	0 / 48 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	2
Urticaria excerbation/ worsening CSU
subjects affected / exposed	4 / 48 (8.33%)	3 / 25 (12.00%)
occurrences all number	22	3
Psychiatric disorders
Restless/ unrest
subjects affected / exposed	0 / 48 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	2
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 48 (4.17%)	2 / 25 (8.00%)
occurrences all number	3	2
Infections and infestations
Upper respiratory tract infections
subjects affected / exposed	14 / 48 (29.17%)	10 / 25 (40.00%)
occurrences all number	18	19
Herpes labialis reactivation
subjects affected / exposed	2 / 48 (4.17%)	1 / 25 (4.00%)
occurrences all number	3	1
Urinary tract Infection/Cystitis/Hämaturie
subjects affected / exposed	5 / 48 (10.42%)	5 / 25 (20.00%)
occurrences all number	5	6

More information

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Were there any global substantial amendments to the protocol? Yes

08 May 2019

new protocol version 2.0: change of exclusion criteria, Assessment schedule and of adress of laboratory for BHRA analysis

18 Dec 2019

new protocol version 3.0: change then umber of participating centers: “aproximately 6 study centers” replaces “3 study centers”, - study duration prolonged to “Last subject last visit”: Q2 2021

13 May 2020

new protocol version 4.0: Changes related to COVID-19: - Training of of study subjects in selfapplication of IMP - Possibility for self-application of IMP at home in combination with telephone based visits - Adjustment of table of assessments - Adjustment of rules for rescreening of patients adjustment of table of assessments - Adjustments of rules for rescreening of patient

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A multicenter, randomized, double-blind, placebo-controlled, phase 2, 16-week treatment study with a 16 week follow-up period to assess the efficacy and safety of Dupilumab (anti-IL4Ra) in adult patients with chronic spontaneous urticaria despite H1-antihistamine treatment.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: change in urticaria activity score 7 (UAS7)

Primary: change in urticaria activity score 7 (UAS7)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A multicenter, randomized, double-blind, placebo-controlled, phase 2, 16-week treatment study with a 16 week follow-up period to assess the efficacy and safety of Dupilumab (anti-IL4Ra) in adult patients with chronic spontaneous urticaria despite H1-antihistamine treatment.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: change in urticaria activity score 7 (UAS7)

Primary: change in urticaria activity score 7 (UAS7)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A multicenter, randomized, double-blind, placebo-controlled, phase 2, 16-week treatment study with a 16 week follow-up period to assess the efficacy and safety of Dupilumab (anti-IL4Ra) in adult patients with chronic spontaneous urticaria despite H1-antihistamine treatment.