Clinical Trials Register

Summary
EudraCT Number:	2019-001561-32
Sponsor's Protocol Code Number:	201900237
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-01-20
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

Netherlands - Competent Authority

A.2

EudraCT number

2019-001561-32

A.3

Full title of the trial

Dupilumab in adults with severe chronic hand eczema with an inadequate response or intolerance to alitretinoin: a randomized, double-blind, placebo-controlled proof of concept efficacy study

A.3.1

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

Dupilumab in severe chronic hand eczema patients who do not respond or are intolerant to alitretinoin

A.4.1

Sponsor's protocol code number

201900237

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	University Medical Center Groningen
B.1.3.4	Country	Netherlands
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	Genzyme Europe B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Groningen
B.5.2	Functional name of contact point	Marie-Louise Schuttelaar
B.5.3	Address:
B.5.3.1	Street Address	Hanzeplein 1
B.5.3.2	Town/ city	Groningen
B.5.3.3	Post code	9713GZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31503612520
B.5.5	Fax number	+31503619247
B.5.6	E-mail	m.l.a.schuttelaar@umcg.nl

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	Dupixent
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis Groupe
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.11 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hand eczema

E.1.1.1

Medical condition in easily understood language

Hand eczema

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10066695
E.1.2	Term	Chronic hand dermatitis
E.1.2	System Organ Class	100000004858

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10036145
E.1.2	Term	Pompholyx eczema
E.1.2	System Organ Class	100000004858

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 evaluate the efficacy of dupilumab in patients with inflammatory subtypes of severe chronic hand eczema with an inadequate response or intolerance to alitretinoin.

E.2.2

Secondary objectives of the trial

To evaluate health related quality of life; to evaluate improvement in severity of hand eczema, assessed by the patient; to evaluate work productivity and impairment.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Title: The effect of dupilumab on the molecular signature of hand eczema
Date: 08-09-2019
Version: 1.0
Objectives:
• To compare genomic changes due to dupilumab in active HE lesions and changes in the HE transcriptome defined by gene expression differences between lesional and non-lesional skin between and within cases at week 16 to baseline.
• To compare treatment-related changesof treatment-related changes in the serum biomarkers including CCL17, CCL18, periostin, ECP, total IgE and allergen-specific IgEs at week 16 to baseline .
• To compare the effects of dupilumab treatment on histologic morphology, including the effect on epidermal hyperplasia at week 16 to baseline.
• To compare the effects of dupilumab treatment on the microbiome colonization profiles between lesional and non-lesional samples (between and within cases) at week 16 compared to baseline.

E.3

Principal inclusion criteria

• Age ≥ 18 years and ≤ 75 years.
• Severe or very severe chronic hand eczema as defined by a Physician Global Assessment (PGA) using a validated Photoguide.
• Inflammatory subtypes of hand eczema: recurrent vesicular hand eczema or chronic fissured hand eczema.
• An inadequate response to topical corticosteroids within 6 months before screening.
• A history of prior alitretinoin exposure and inadequate response or intolerance to alitretinoin.
• Patients has also received standard skin care, including emollients and barrier protection as appropriate, without significant improvement.
• Patients has avoided irritants and contact allergens, if identified, without significant improvement.
• Women of childbearing potential are required to use a highly effective (failure rate of <1% per year when used consistently and correctly) method of birth control, prior to receiving study intervention, during the study and for at least 12 weeks after receiving the last administration of study intervention. E.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal foam/gel/film/cream/suppository (if available in their locale); male partner sterilization (the vasectomized partner should be the sole partner for that participant); true abstinence (when this is in line with the preferred and usual lifestyle of the participant). NOTE: If a female participant’s childbearing potential changes after start of the study (eg, a woman who is not heterosexually active becomes active, a premenarchal woman experiences menarche), she must begin practicing a highly effective method of birth control, as described above.
• A woman of childbearing potential must have a negative serum or urine pregnancy test (β-human chorionic gonadotropin [β-hCG]) at screening and at Week 0 prior to administration of study intervention;
• Agree not to receive a live virus or live bacterial vaccination during the study, or within 12 weeks after the last administration of study intervention.
• Agree not to receive a BCG vaccination during the study, or within 12 months after the last administration of study intervention.
• Be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
• Must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study, and is willing to participate in the study.

E.4

Principal exclusion criteria

• Other clinical subtypes of hand eczema, e.g. hyperkeratotic hand eczema, as defined by the Danish Contact Dermatitis Group.
• Treatment with alitretinoin, systemic immunosuppressive medication or UV radiation within the previous 4 weeks.
• Patients with predominantly atopic dermatitis, in whom the hands are also involved, but no main concern.
• Patients with controlled atopic dermatitis, in which the hands are mainly affected, are eligible for inclusion.
• Psoriasis of the hands.
• Active bacterial, fungal, or viral infection of the hands.
• Pregnant/lactating or planning to become pregnant during the study period.
• Current malignancy (other than successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma and⁄or localized carcinoma in situ of the cervix).
• Participant has known allergies, hypersensitivity, or intolerance to dupilumab or its excipients: L-arginine hydrochloride, L-histidine, polysorbate 80, sodium acetate, acetic acid, sucrose, water for injections.
• Participants with active helminth and other parasitic infections.
• Patients infected with human immunodeficiency virus (HIV), positive serology for HIV antibody).
• Patients testing positive for hepatitis B virus (HBV) or hepatitis C (HCV) infection.

E.5 End points

E.5.1

Primary end point(s)

• Response to treatment is defined as an improvement of ≥ 2 steps on the PGA. Very severe hand eczema is defined as responding to treatment if a status of at least ‘moderate’ is achieved. Severe hand eczema is defined as responding to treatment if a status of at least ‘almost clear’ is achieved. The PGA, based on a validated Photoguide developed by Coenraads et al, covers 5 degrees of severity (clear, almost clear, moderate, severe, very severe) and takes into account the intensity of clinical signs and percentage of hand surface involved.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline and week 16 visit.

E.5.2

Secondary end point(s)

Severity of hand eczema
• The difference of the Hand Eczema Severity Index (HECSI) score between baseline and week 4, 8, 12 and 16 respectively. The HECSI is an objective severity assessment based on clinical symptoms only. It includes erythema, fissures, vesicles, scaling, oedema, papules and measurement of the affected area. The score ranges from 0-360, with a score > 28 indicating severe hand eczema.

Quality of life
• The difference of The Quality Of Life in Hand Eczema Questionnaire (QOLHEQ) score between baseline and week 4, 8, 12 and 16 respectively. The QOLHEQ is a multi-domain disease specific instrument for hand eczema assessing impairments in quality of life. The score ranges from 0-120, with 120 indicating worst quality of life.
• The difference between the Dermatology Life Quality Index score between baseline and week 4, 8, 12 and 16 respectively.

Patient reported improvement
• Patient Global Assessment (PaGA) in patients reporting improvement as ‘clear or almost clear’ compared to baseline at week 4, 8 and 16. The PaGA takes signs and symptoms into account. It covers 6 degrees of improvement: ‘clear or almost clear’ (at least 90% clearing of disease signs and symptoms compared to baseline), ‘marked improvement’ (at least 75% clearing), ‘moderate improvement’ (at least 50% clearing), ‘mild improvement’ (at least 25% clearing), ‘no change’, or ‘worsening’.

Work productivity and impairment
• Work productivity and impairment questionnaire (WPAI) at week 16 compared to baseline.

Exploratory assessments (substudy)
• Comparison to baseline of genomic changes due to dupilumab at week 16 in active HE lesions and changes in the HE transcriptome defined by gene expression differences between lesional and non-lesional skin between and within cases.
• Comparison to baseline of the effects of dupilumab treatment at week 16 on histologic morphology, including the effect on epidermal hyperplasia.
• Comparison to baseline of treatment-related changes at week 16 in the serum biomarkers including CCL17, CCL18, periostin, ECP, total IgE and allergen-specific IgEs.
• Comparison to baseline of microbiome colonization profiles at week 16 between lesional and non-lesional samples (between and within cases).

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline, week 4, week 8, week 12 and week 16 visit.

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

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

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)

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

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.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

2020-01-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-28

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

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