Clinical Trials Register

Summary
EudraCT Number:	2020-003542-36
Sponsor's Protocol Code Number:	LPS16763
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:	2020-10-16
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

2020-003542-36

A.3

Full title of the trial

A multi-center, exploratory study to assess dupilumab effect on pruritus neuro-mechanisms in patients with atopic dermatitis

A.3.1

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

Dupilumab effect on pruritus neuro-mechanisms in patients with atopic dermatitis

A.3.2

Name or abbreviated title of the trial where available

DIFFEREN-STAD

A.4.1

Sponsor's protocol code number

LPS16763

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1251-5658

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.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Atopic Dermatitis

E.1.1.1

Medical condition in easily understood language

Atopic Dermatitis

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	10012438
E.1.2	Term	Dermatitis atopic
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

Assess change in neuronal architecture following long term treatment with dupilumab in skin biopsies from atopic dermatitis (AD) participants with chronic pruritus

E.2.2

Secondary objectives of the trial

- Assess change in neuronal architecture following short term treatment with dupilumab and during follow-up in skin biopsies from AD participants with chronic pruritus
- To evaluate the efficacy of dupilumab in AD participants with chronic puritus
- To evaluate the safety of dupilumab in adult participants with moderate-to-severe AD

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For Atopic dermatitis patients
Male or female of ≥18 years of age inclusive, at the time of signing the informed consent form (ICF).
Diagnosed with moderate-to-severe chronic AD for at least 1 year before screening.
Eligible to be treated with dupilumab according to product monograph.
Pruritus lasting 6 or more weeks before baseline (Day 1).
Eczema Area and Severity Index (EASI) score ≥12 at baseline.
Pruritus numerical rating scale (NRS) ≥4 at baseline.
Investigator global assessment (IGA) score of ≥3 at screening (on the 0 to 4 scale) at baseline.
Atopic dermatitis active lesions on the upper limbs or lower limbs suitable for a skin biopsy without oozing, bleeding, or infection on upper limbs or trunk.
Patients with acute AD lesions as determined by Investigator’s judgment.
Stable treatment with non-prohibited medication or therapy during the study.

For Healthy participants
Male or female of ≥18 years of age inclusive, at the time of signing the ICF.
Certified as generally healthy by a comprehensive clinical assessment

E.4

Principal exclusion criteria

For atopic dermatitis patients
Previous treatment with dupilumab stopped within 6 months of baseline due to inadequate response to dupilumab.
Skin conditions other than AD that can confound assessments in the opinion of theinvestigator.
Regular use (>2 visits per week) of a tanning booth/parlor within 4 weeks of the Screening Visit.
Severe concomitant illness(es) that, in the Investigator’s judgment, would adversely affect the patient’s participation in the study.
Patients with active tuberculosis (TB) or non-TB mycobacterial infection, or a history of incompletely treated TB unless it is well documented the participant has been adequately treated and can now start treatment with a biologic agent
Diagnosed with, suspected of, or at high risk of endoparasitic infection, and/or use of antiparasitic drug within 2 weeks before the Screening Visit (Visit 1) or during the Screening Period.
Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals,or antifungals within 2 weeks before the Screening Visit (Visit 1) or during the Screening Period.
Known or suspected immunodeficiency, including history of invasive opportunistic infections
Active malignancy or history of malignancy within 5 years before the Baseline Visit, except completely treated in situ carcinoma of the cervix and completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin.
Ocular disorder that in the opinion of the Investigator could adversely affect the individual’s risk for study participation. Examples include, but are not limited to,individuals with a history of active cases of herpes keratitis, Sjogren’s syndrome, keratoconjunctivitis sicca or dry eye syndrome that require daily use of supplemental lubrication or individuals with ocular conditions that require the use of ocular corticosteroids or cyclosporine.
History of systemic hypersensitivity or anaphylaxis to dupilumab or any other biologic therapy, including any excipient.
Participant with any other medical or psychological condition including relevant laboratory or electrocardiogram abnormalities at screening

For healthy participants
Regular use (>2 visits per week) of a tanning booth/ parlor within 4 weeks of the Screening
Visit
Treatment with the following concomitant medications and procedures is prohibited within 4 weeks before the Screening Visit or 5 half-lives (whichever is longer) until EoS Visit:-
Topical medication.
Analgesics.
Immunomodulators.
Antidepressants.
Anti-anxiety drugs.
Any Type 2 immune disorders uncontrolled Type 2 diabetes mellitus, Type 1 diabetes mellitus, neuropathy or any other neurological disease.
Any concomitant illness(es) or conditions that, in the Investigator’s judgment, would
adversely affect the subject’s participation in the study or potentially affect any skin biopsy
related read out.
Positive test for immunoglobulin E (IgE) antibodies.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

1, 2 - baseline to week 17

E.5.2

Secondary end point(s)

1 - Change from baseline in intraepidermal nerve fiber density ; Quantification of intraepidermal nerve fiber density will be calculated by assessing nerve fibers crossing the basement membrane per square millimetre (F/mm2)
2 - Change from baseline in nerve fiber branching ; Branching of nerve fibers will be assessed semi-quantitatively by classifying patients into 4 groups comprised of only linear, mainly linear, mainly branched or only branched fibers.
3 - Change from baseline in the outcome of peak pruritus assessed by numeric rating scale (NRS) ; The peak pruritus NRS is a simple assessment tool that participants ≥ 12 to <18 years old will use to report the intensity of their pruritus (itch) ranges from 0 to 10 with 0 being 'no itch' and 10 being the' worst itch imaginable''
4 - Change from baseline in the outcome of eczema and severity index (EASI) ; The EASI is a composite index with scores ranging from 0 to 72. Higher scores indicates worse condition
5 - Change from baseline in the outcome of scoring atopic dermatitis (SCORAD ; SCORAD was used to assess the extent and severity of AD. Extent and severity of eczema as well as subjective assessment of symptoms were assessed and scored. SCORAD total score ranges from 0 (absent disease) to 103 (severe disease).
6 - Change from baseline in the outcome of Patient-Reported Outcomes Measurement Information (PROMIS-itch ; PROMIS-itch is an assessment of itch . The short form of following item will be used with no summary score.
Itch-severity; activity and clothing; mood and sleep; interference; scratching behavior; quality; trigger.
7 - Change from baseline in the outcome of Patient Oriented Eczema Measure (POEM) ; POEM is a 7-item (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) questionnaire to assess frequency of disdase symptoms with a scoring system of 0 to 28. The higher score indicating higher severiy
8 - Change from baseline in the outcome of Patient Oriented Eczema Measure Dermatology Life Quality Index (DLQI ; DLQI is a questionaire with a score system of 0 to 30 the high score is indicateive of poor QoL
9 - Change from baseline in the outcome of Atopic Dermatitis Control Tool (ADCT) ; ADCT is a questionnaire to assess patient-self-perceived control of their eczema with a total score from 0 to 24; higher scores indicate lower AD control.
10 - Change from baseline in the outcome of Sleep quality NRS ; Sleep quality NRS is a measure asking patients to rate the quality of their sleep using 0 (worst possible sleep) to 10 (best possible sleep) NRS
11 - Change from baseline in the outcome of Skin Pain NRS ; Skin pain NRS is a measure asking patients to rate their skin pain using a 0 (No pain) to 10 (worst pain possible) NRS
12 - Change from baseline in the outcome of Skin Sensitivity NRS ; Skin sensitivity NRS is a measure asking patient to rate their skin sensitivity to touch using a 0 (Normal) to 10 (extremely sensitive) NRS
13 - Change from baseline in the outcome of Skin Burning NRS ; Skin burning NRS is a measure asking patients to rate the burning sensation of thir skin using a 0 (Not at all) to 10 (ver much) NRS
14 - Proportion of AD participants reaching pruritus NRS ≥4 point
improvement from baseline
15 - Incidence of treatment-emergent adverse events

E.5.2.1

Timepoint(s) of evaluation of this end point

1, 2 - baseline to weeks 3 and 21
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 - baseline to weeks 17 and 21
14 - baseline to weeks 3, 5, 9, 17, and 21
15 - baseline to week 21

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

Yes

E.6.13.1

Other scope of the trial description

Exploratory research

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

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.8.1.7.1

Other trial design description

Healthy participants will serve as control group

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

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

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

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

United States

Germany

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 months

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:

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-10-16.

Yes

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.3.3.6.1

Details of subjects incapable of giving consent

WOCBP not using contraception will be included in the healthy control arm only, which will not receive any study drug

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

F.4.2.2

In the whole clinical trial

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

2021-01-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-08-17

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