Clinical Trial to Evaluate Efficacy and Safety of Dupilumab in Localized Scleroderma (DupiMorph)

A Randomized, Placebo-controlled Phase IIa Clinical Trial to Evaluate the Efficacy and Safety of Subcutaneous Dupilumab in Localized Scleroderma

The DupiMorph study evaluates the efficacy of Dupilumab in localized scleroderma patients. Dupilumab is approved in the US and EU for the treatment of moderate/severe atopic dermatitis and since 2018 in the US for severe asthma therapy.

Study Overview

• Status: Recruiting
• Conditions: Localized Scleroderma
• Intervention / Treatment: Drug: Dupilumab 300Mg Solution for Injection; Other: Placebo

Detailed Description

Localized scleroderma (LS) comprises a heterogenous group of sclerotic skin disorders. The incidence of LS is reported to be approximately 27 cases/ 1x106 and is hence approximately 2-3-fold higher compared to systemic scleroderma. Although in most cases not lethal the disease can significantly impact quality of life. Depending on the location of fibrosis, the disorder can cause bone deformities, alopecia, skin atrophy or lesions with severe hypo-/hyperpigmentation.

The disease is pathomechanistically poorly understood and no effective therapy is currently approved. The most promising treatments up to date include methotrexate ± pulsed corticosteroids or phototherapy with PUVA or UVA1. Yet, the number of treated patients in these studies is low. The response rates are low and inconsistent with approximately 50% of patients treated with UVA1 experience a recurrence within three years. There are no studies on efficacy of topical corticosteroids in LS. Small pilot studies and few case reports describe regression of lesions after topical calcineurin inhibitors. In addition, current therapies can only be applied for a short time during the acute phase due to the side effect profile after long-term use (e.g. skin atrophy in response to topical steroids, skin cancer in response to long term UV therapy, multiple side effects by long- term use of methotrexate and/or corticosteroids). Hence, this study evaluates, in comparison with placebo, the efficacy of Dupilumab administered subcutaneously every 14 days in patients with Morphea (plaque type) or generalized localized scleroderma (affecting at least three anatomic sites).

• Study Type: Interventional
• Enrollment (Anticipated): 45
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sabine Schleicher, Dr.; Phone Number: 88793 0049 221 478; Email: sabine.schleicher1@uk-koeln.de

Study Locations

• Germany
  • Köln, Germany, 50924
    • Recruiting
    • Uniklinik Köln, Klinik für Dermatologie und Venerologie
    • Contact: Sabine Eming, Prof. Dr.; Phone Number: 3196 0049 221 478; Email: sabine.eming@uni-koeln.de
    • Contact: Nicolas Hunzelmann, Prof. Dr.; Phone Number: 4517 0049 221 478; Email: nico.hunzelmann@uni-koeln.de
    • Principal Investigator: Sabine Eming, Prof. Dr.
    • Principal Investigator: Nicolas Hunzelmann, Prof. Dr.
    • Sub-Investigator: Pia Moinzadeh, PD Dr.
    • Sub-Investigator: Judith Kästle
    • Sub-Investigator: Phillip Szudybill
  • Oberhausen, Germany, 46045
    • Recruiting
    • Helios St. Elisabeth Klinik Oberhausen, Klinik für Dermatologie, Venerologie und Allergologie
    • Contact: Alexander Kreuter, Prof. Dr.; Phone Number: 8002 0049 208 8508; Email: alexander.kreuter@helios-gesundheit.de
    • Contact: Christian Tigges, Dr.; Phone Number: 8016 0049 208 8508; Email: christian.tigges@helios-gesundheit.de
    • Principal Investigator: Alexander Kreuter, Prof. Dr.
    • Principal Investigator: Christian Tigges, Dr.
    • Sub-Investigator: Alena-Lioba Michalowitz
    • Sub-Investigator: Bijan Koushk, Dr.
  • Tübingen, Germany, 72076
    • Recruiting
    • Universitäts-Hautklinik Tübingen
    • Contact: Matthias Hahn, Dr.; Phone Number: 0049 7071 29; Email: matthias.hahn@med.uni-tuebingen.de
    • Contact: Thomas Eigentler, Prof. Dr.; Phone Number: 85748 0049 7071 29; Email: thomas.eigentler@med.uni-tuebingen.de
    • Principal Investigator: Matthias Hahn, Dr.
    • Principal Investigator: Thomas Eigentler, Prof. Dr.
    • Sub-Investigator: Martin Röcken, Prof. Dr.
    • Sub-Investigator: Benjamin Walz, Dr.
    • Sub-Investigator: Isabel Grethel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject is a male or female ≥18 years of age on the day the study informed consent is signed
• Out-patient status
• Caucasian
• Morphea (plaque type) or Generalized localized scleroderma (affecting at least three anatomic sites)
• At least one lesions with lilac ring (active phase of the disease);
• Activity of LS within the last 12 month (as defined by progression of size or new developing plaque)
• For women of childbearing potential: negative pregnancy test at Visit 1
• For women of childbearing potential: Use of effective method of contraception from 4 weeks prior to enrolment, throughout study treatment until 12 weeks after the last IMP dose.
• Written informed consent signed

Exclusion Criteria:

• Systemic immunosuppressive therapy or UV therapy less than 3 months before enrollment.
• Participation in another trial of IMPs or devices parallel to, or less than 6 months before or previous participation in this trial
• Pregnancy or breastfeeding mother
• Diagnosis of other significant chronic inflammatory or autoimmune disorders. Patients with the following autoimmune disorders are excluded from the study: Multiple sclerosis, primary biliary cirrhosis, type I diabetes mellitus. Patients with the following autoimmune disorders are regarded as eligible: Lichen sclerosus, vitiligo, alopecia arthritis, thyroid diseases (e.g. Hashimoto disease). Patients with any autoimmune disorder not listed above should only be included after consultation with the principal coordinating investigator.
• Topical immunosuppressive therapy less than 1 month before enrollment
• Concurrent phototherapy
• Known infection with helminths (helminthosis)
• Any condition or laboratory abnormality that, in the judgment of the investigator, would put the subject at unacceptable risk for participation in the study or may interfere with the assessments included in the study. E.g. uncontrolled psychiatric illness or history of clinical relevant drug abuse.
• Known hypersensitivity to any components of the IMP
• Treatment with a live (attenuated) vaccine within 3 months prior to enrollment
• History of malignancy (except patients with completely treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin)
• Known diagnosis of active tuberculosis or non-tuberculous mycobacterial infection or latent untreated tuberculosis unless it is well documented by a specialist that the patient has been adequately treated
• Known diagnosis of HIV, HBV or HCV infection
• Regular use (more than 2 visits per week) of a tanning booth/parlor
• Known diagnosis of asthma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dupilumab; 30 patients; Dupilumab s.c. injection; 2 ready-to-use syringes (600 mg) initial (V1), 1 ready-to-use syringe (300 mg) every 14 days (V2- V13) Dupilumab s.c. injection in healthy skin, 24 weeks	Drug: Dupilumab 300Mg Solution for Injection; First dose: 600 mg (2 syringes); subsequent doses: 300 mg (1 syringe); Other Names: Dupixent
Placebo Comparator: Placebo; 15 patients; placebo s.c. injection; 2 ready-to-use syringes initial (V1), 1 ready-to-use syringe every 14 days (V2-V13) placebo s.c. injection in healthy skin, 24 weeks	Other: Placebo; First dose: 2 syringes, no active substance; subsequent doses: 1 syringe, no active substance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LoSCAT target lesion	Treatment response is assessed using the LoSCAT (Localized Scleroderma Cutaneous Assessment Tool). Target lesion will be assessed at Baseline and End of Treatment. Score reduction by 50% after 24 weeks (End of Treatment Visit V14) compared to Baseline Visit (V1) is defined as treatment response.	Baseline to End of Treatment Visit, 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mLoSSI all lesions	Change in mLoSSI (Localized Scleroderma Skin Activity Index) of all existing lesions during treatment, at End of Treatment Visit and during follow-up	Baseline to Follow-Up Visit, 48 weeks
LoSDI all lesions	Change in LoSDI (Localized Scleroderma Skin Damage Index) of all existing lesions during treatment, at End of Treatment Visit and during follow-up	Baseline to Follow-Up Visit, 48 weeks
Number of lesions	Count of all existing non-target and new lesions on the entire integument during treatment, at End of Treatment Visit and during follow-up	Baseline to Follow-Up Visit, 48 weeks
DLQI	Change in DermatoLogy Quality of life Index (DLQI). The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired.	Baseline to Follow-Up Visit, 48 weeks
RNAseq	Gene signature of localized scleroderma after Dupilumab treatment: RNA- seq of tissue biopsies obtained from the lesion (lilac ring, optional: center) before (baseline visit V1) and after treatment (EoT V14) and healthy skin before treatment	Baseline to End of Treatment Visit, 24 weeks
RT-qPCR	Quantification of change in gene expression of genes identified by RNAseq in tissue of localized scleroderma patients after Dupilumab treatment: RT-qPCR of tissue biopsies obtained from the lesion (lilac ring, optional: center) before (baseline visit V1) and after treatment (End of Treatment Visit V14) and healthy skin before treatment	Baseline to End of Treatment Visit, 24 weeks
Adverse events (AEs)	Adverse events will be documented throughout the study	Baseline to Follow-Up Visit, 48 weeks
Physical examination	Physical examination (general appearance including skin, head and throat (head, eyes, ears, nose, and throat), lymph nodes, respiratory, cardiovascular, musculoskeletal, and neurological systems) will be documented throughout the study.	Baseline to Follow-Up Visit, 48 weeks
Body weight	Body weight will be documented throughout the study.	Baseline to Follow-Up Visit, 48 weeks
Blood pressure	Blood pressure will be documented throughout the study.	Baseline to Follow-Up Visit, 48 weeks
Pulse rate	Pulse rate will be documented throughout the study.	Baseline to Follow-Up Visit, 48 weeks
Body temperature	Body temperature will be documented throughout the study.	Baseline to Follow-Up Visit, 48 weeks
Haematocrit (HcT)	Haematocrit (HcT) will be documented at End of Treatment Visit and during follow-up	Baseline to Follow-Up Visit, 48 weeks
Haemoglobin	Haemoglobin (Hgb) will be documented at End of Treatment Visit and during follow-up	Baseline to Follow-Up Visit, 48 weeks
Blood cell count	Platelet count and differential White blood cell count will be documented at End of Treatment Visit and during follow-up	Baseline to Follow-Up Visit, 48 weeks
Blood Enzymes	Clinical Chemistry parameters (Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Gamma-glutamyl transferase (GGT), Lactic dehydrogenase (LDH)) will be documented at End of Treatment Visit and during follow-up	Baseline to Follow-Up Visit, 48 weeks
Clinical Chemistry	Clinical Chemistry parameters (Creatinine) will be documented at End of Treatment Visit and during follow-up	Baseline to Follow-Up Visit, 48 weeks
Anti-nuclear antibodies (ANAs) levels	Change in anti-nuclear antibodies (ANAs) levels	Baseline to Follow-Up Visit, 48 weeks
Serum cytokine levels	Change in serum levels of IL-4, IL-5, IL-13, periostin, dipeptidyl peptidase-4	Baseline to Follow-Up Visit, 48 weeks

Collaborators and Investigators

• Sponsor: University of Cologne
• Investigators: Principal Investigator: Sabine Eming, Prof. Dr., University of Cologne

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2020
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): June 1, 2025

Study Registration Dates

• First Submitted: December 10, 2019
• First Submitted That Met QC Criteria: December 13, 2019
• First Posted (Actual): December 16, 2019

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Morphea
• Additional Relevant MeSH Terms: Skin Diseases; Connective Tissue Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized
• Other Study ID Numbers: Uni-Koeln-3815; 2019-002036-90 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No