Lenalidomide vs Methotrexate in Difficult-to-treat Cutaneous Lupus Erythematosus (LEISURE)

Lenalidomide vs mEthotrexate in dIfficult-to-treat cutaneouS lUpus eRythEmatosus : An Assessor-blinded Randomized Clinical Trial

Cutaneous lupus erythematosus (CLE) is a heterogeneous inflammatory autoimmune disease associated or not with systemic lupus erythematosus (SLE). Active CLE often cause pain/burning sensation and may lead to permanent visible scars and cicatricial alopecia, with psycho-social consequences/poor quality of life. First-line antimalarials (AMs) are recommended in CLE in addition to topical corticosteroids/tacrolimus with long-term response rate around 50%. Oral glucocorticosteroids (GCs) are recommended in addition to AMs for short term therapy in severe or widespread active CLE lesions. In non-responders to AMs and low-dose oral GCs, i.e., difficult-to-treat CLE, guidelines recommend the add-on of methotrexate as preferential second-line agent, with an overall efficacy of 50% in observational studies. Thalidomide has shown response rate of ≈90% in CLE in a meta-analysis of observational studies and is recommended as a second or third-line agent. However, potential severe adverse events (AEs) including teratogenicity, peripheral neuropathy and thromboembolic events limit its use.

Biological therapies including belimumab and anifrolumab, are approved only for patients with associated SLE (and not for those with isolated CLE). Their efficacy has been demonstrated as add-on therapy versus placebo but not versus a comparative drug. Moreover, efficacy of belimumab seems limited in difficult to-treat CLE and has not been assessed using validated tool, as the Cutaneous Lupus Erythematosus Disease Area and Severity (CLASI) Index. Anifrolumab seems interesting in CLE associated with SLE, but its use is limited by monthly intravenous infusions, high cost and unknown long-term AEs. Moreover, its efficacy in isolated CLE has not been assessed.

Lenalidomide is a thalidomide analogue with in vitro 1000 more potent immunomodulatory properties. It is recommended as a third-line treatment in France. With more than 60 treated patients, it showed excellent and rapid efficacy with an absence of drowsiness and peripheral neuropathy with a low-dose regimen of 5 mg/day. The use of lenalidomide was to date limited by its very high cost and its indications were restricted to haematological disorders. For note, the prevention of the higher risk of thromboembolism with lenalidomide requires the daily use of low-dose aspirin.

In France, a generic of lenalidomide is now available with a monthly cost of 2 euros, allowing a broad-scale assessment of its efficacy. Finally, lenalidomide might have a better efficacy than methotrexate.

We hypothesize that lenalidomide would be more efficacious than methotrexate in difficult-to-treat CLE patients with or without associated SLE. We assume that such trial would not be supported by pharmaceutical companies.

Study Overview

• Status: Not yet recruiting
• Conditions: Cutaneous Lupus Erythematosus (CLE)
• Intervention / Treatment: Drug: Lenalidomide; Drug: Methotrexate (MTX)

• Study Type: Interventional
• Enrollment (Estimated): 122
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: François CHASSET; Phone Number: +33156017225; Email: francois.chasset@aphp.fr
• Study Contact Backup: Name: Olivier CHOSIDOW; Phone Number: 0142163131; Email: olivier.chosidow@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients of at least 18 years of age
2. Affiliated to the French social security
3. Able to provide written informed consent
4. Histologically-confirmed diagnosis of active CLE with or without associated SLE, either historical or at screening
5. CLASI-A score ≥ 8 at both screening and randomization

6. Active CLE despite

   • AMs agents used for at least 3 months and at stable dose for at least 30 days prior to randomization or previously documented discontinuation of AMs due to poor tolerability an/or side effect and/or
   • stable dose of GCs ≤15mg/day and/or
   • stable dose of topical corticosteroids (TCS) or topical tacrolimus for at least 30 days prior to randomization
7. Accepting monthly plasma pregnancy test and using adequate contraception for at least 4 weeks before and until 4 weeks following treatment

Exclusion Criteria:

1. Kidney function, liver function, cell blood count and infectious serology incompatible with receiving the study treatments, according to the SMPC of each drug.
2. Alcoholism (1/ no more than 10 standard drinks per week, 2/ no more than two standard drinks per day, and 3/ at least two alcohol-free days every week)
3. Ongoing cancer, including solid tumors and hematologic malignancies
4. Active severe SLE features including lupus nephritis, neuropsychiatric SLE, serositis, severe haematological features (autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura) requiring high dose oral or IV GC and/or mycophenolate mofetil or cyclophosphamide

5. Medications:

   • Previous failure of methotrexate and lenalidomide prescribed for active CLE
   • Use of classical immunosuppressant drugs (mycophenolate mofetil, azathioprine), thalidomide, dapsone, retinoids, Janus Kinase inhibitors for CLE or SLE 4 weeks before screening
   • Use of biological therapy for CLE or SLE (including belimumab, rituximab, obinituzumab, ustekinumab, anifrolumab) 12 weeks before screening
6. Contraindication to use low-dose aspirin: salicylate hypersensitivity, salicylate-induced asthma, constitutional or acquired bleeding disorder, active gastroduodenal ulcer, or history of digestive bleeding.
7. Arterial or unprovoked venous thromboembolic events ≤ 5 years (for note antiphospholipid syndrome treated with vitamin K antagonist without thromboembolic events in the last 5 years or patients with positive antiphospholipid autoantibodies will NOT be excluded)
8. Pregnant women, breastfeeding or planning to become pregnant during the study treatment period and 1 month after the last dose of study treatment
9. Patients under legal protection and inability to comply with study requirement

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: Lenalidomide with aspirin; Lenalidomide with low-dose aspirin	Drug: Lenalidomide; Lenalidomide with oral dose of 5 mg/day during 16 weeks associated with low-dose aspirin of 100 mg/day except for patients already receiving anticoagulant therapy
Active Comparator: Methotrexate with folic acid; Methotrexate with low dose of folic acid	Drug: Methotrexate (MTX); Methotrexate oral dose of 15 mg per week for individuals < 80 kg, and a dose of 20mg per week for those over 80 kg, along with an equal dose of folic acid supplementation given 48 hours after each dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients who achieve decrease of at least 50% from baseline in the CLASI activity (CLASI-A) score	CLASI : Cutaneous LE disease Area and Severity Index	At week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients reaching CLASI-A 70	CLASI : Cutaneous LE disease Area and Severity Index	At week 16
Proportion of participants who achieve complete or almost complete response (CLASI-A 0-3)	CLASI : Cutaneous LE disease Area and Severity Index	At week 16
Percentage of patients reaching CLASI-A 70	CLASI : Cutaneous LE disease Area and Severity Index	At week 24
Proportion of participants who achieve complete or almost complete response (CLASI-A 0-3)	CLASI : Cutaneous LE disease Area and Severity Index	At week 24
Variation of Quality of life using DLQI	DLQI : Dermatology Life Quality Index	At week 16
Variation of Quality of life using DLQI	DLQI : Dermatology Life Quality Index	At week 24
SLE activity using SLEDAI	SLEDAI : Systemic Lupus Erythematosus Disease Activity Index	Up to 24 weeks
SLE flare using SENELA-SLEDAI Flare Index (SFI)	SELENA : Safety of Estrogens in Lupus Erythematosus National Assessment SLEDAI : Systemic Lupus Erythematosus Disease Activity Index	Up to 24 weeks
Variation of GCs dose		Between inclusion and week 24.
Variation of damage in each group using CLASI-D	CLASI : Cutaneous LE disease Area and Severity Index	At week 24
Variation of damage in each group using CLASI-D	CLASI : Cutaneous LE disease Area and Severity Index	At week 16
Rate of adverse events		Up to 24 weeks

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2025
• Primary Completion (Estimated): February 1, 2029
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: February 10, 2025
• First Submitted That Met QC Criteria: May 7, 2025
• First Posted (Actual): May 11, 2025

Study Record Updates

• Last Update Posted (Actual): May 11, 2025
• Last Update Submitted That Met QC Criteria: May 7, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: lenalidomide; systemic lupus erythematosus; methotrexate; cutaneous lupus erythematosus; chronic CLE; Resistance to anti-malarial
• Additional Relevant MeSH Terms: Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Skin Diseases; Lupus Erythematosus, Systemic; Lupus Erythematosus, Cutaneous; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide; Methotrexate
• Other Study ID Numbers: APHP240920; 2024-520089-70-00 (Ctis)

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
• product manufactured in and exported from the U.S.: No