The WILLOW Study With M5049 in SLE and CLE (SCLE and/or DLE) (WILLOW)

Study Overview
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Brief Summary
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The purpose of this Proof of Concept (PoC) and Dose-finding (DF) basket study is to evaluate the efficacy and safety of orally administered Enpatoran over 24 weeks in systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE; subacute cutaneous lupus erythematosus [SCLE] and/or discoid lupus erythematosus [DLE]) participants in a randomized, double-blind, placebo-controlled, parallel, adaptive and dose-ranging setting. Study Duration: 33 weeks Visit Frequency: every 2 or 4 weeks Enpatoran is not available through an expanded access program.

Official Title
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A Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging, Parallel and Adaptive Study to Evaluate the Efficacy and Safety of Enpatoran in SLE and in CLE (SCLE and/or DLE) Participants Receiving Standard of Care (WILLOW)

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Enpatoran low dose
* Drug: Enpatoran medium dose
* Drug: Enpatoran high dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Active CLE (SCLE and/or DLE) with a CLE disease area and activity index (CLASI-A) >= 8 Active SLE with presence of: CLASI-A >= 8 and BILAG 2004 1B, C, D (that is [i.e.], No BILAG 2004 A and No BILAG 2004 >= 2B) or BILAG 2004 >= 1A or 2B and 1 or 2 of the following: Hybrid Safety of Estrogens in Systemic Lupus Erythematosus National Assessment (SELENA)-SLEDAI >= 6 at Screening Visit and confirmed clinical hybrid SELENA-SLEDAI >= 4 (excluding laboratory parameters) at Day 1 Visit and/or CLASI-A >= 8 Receiving a stable dose of at least one of the following standards of care therapies for lupus: Immunomodulator/immunosuppressant, oral corticosteroids, and/or topical corticosteroids Other protocol defined inclusion criteria could apply Exclusion Criteria: Autoimmune or rheumatic disease other than SLE or CLE Dermatological diseases other than cutaneous manifestations of SLE or CLE Uncontrolled medical conditions including significant cardiovascular events, active lupus nephritis, and active neurological disorder Ongoing or active clinically significant viral, bacterial, or fungal infection History of uncontrolled seizures or other neurological disorder History of or positive for human immunodeficiency virus, hepatitis C virus, or hepatitis B virus History of malignancy Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cohort A: Placebo<br>Participants with CLE (active SCLE and/or DLE) or SLE with predominantly active lupus rash (Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI-A] greater than or equal to [>=] 8) will be enrolled in Cohort A to receive placebo matched to Enpatoran. | Drug: Placebo<br>* Participants will receive placebo matched to Enpatoran up to 24 weeks.<br>|
| Experimental: Cohort A: Enpatoran low dose<br>Participants with CLE (active SCLE and/or DLE) or SLE with predominantly active lupus rash (CLASI-A >= 8) will be enrolled in Cohort A to receive low dose of Enpatoran. | Drug: Enpatoran low dose<br>* Participants will receive film-coated tablets of Enpatoran at a low dose orally, twice daily (BID) up to 24 weeks.<br>* Other names: M5049;|
| Experimental: Cohort A: Enpatoran medium dose<br>Participants with CLE (active SCLE and/or DLE) or SLE with predominantly active lupus rash (CLASI-A >= 8) will be enrolled in Cohort A to receive medium dose of Enpatoran. | Drug: Enpatoran medium dose<br>* Participants will receive film-coated tablets of Enpatoran at a medium dose, orally, BID up to 24 weeks.<br>* Other names: M5049;|
| Experimental: Cohort A: Enpatoran high dose<br>Participants with CLE (active SCLE and/or DLE) or SLE with predominantly active lupus rash (CLASI-A >= 8) will be enrolled in Cohort A to receive high dose of Enpatoran. | Drug: Enpatoran high dose<br>* Participants will receive film-coated tablets of Enpatoran at a high dose, orally, BID up to 24 weeks.<br>* Other names: M5049;|
| Placebo Comparator: Cohort B (Part 1 + Part 2): Placebo<br>Participants with active SLE who have moderate to high systemic disease activity (British Isles Lupus Assessment Group [BILAG A/2B]) with 1 or 2 of the following: CLASI-A >= 8 and/or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) >= 6 will be enrolled in Cohort B to receive placebo matched to Enpatoran . | Drug: Placebo<br>* Participants will receive placebo matched to Enpatoran up to 24 weeks.<br>|
| Experimental: Cohort B (Part 1 + Part 2): Enpatoran high dose<br>Participants with active SLE who have moderate to high systemic disease activity (BILAG A/2B) with 1 or 2 of the following: CLASI-A >= 8 and/or SLEDAI >= 6 will be enrolled in Cohort B to receive high dose of Enpatoran. | Drug: Enpatoran high dose<br>* Participants will receive film-coated tablets of Enpatoran at a high dose, orally, BID up to 24 weeks.<br>* Other names: M5049;|
| Experimental: Cohort B (Part 2): Enpatoran low dose<br>Participants with active SLE who have moderate to high systemic disease activity (BILAG A/2B) with 1 or 2 of the following: CLASI-A >= 8 and/or SLEDAI >= 6 will be enrolled in Cohort B to receive low dose of M5049. | Drug: Enpatoran low dose<br>* Participants will receive film-coated tablets of Enpatoran at a low dose orally, twice daily (BID) up to 24 weeks.<br>* Other names: M5049;|
| Experimental: Cohort B (Part 2): Enpatoran medium dose<br>Participants with active SLE who have moderate to high systemic disease activity (BILAG A/2B) with 1 or 2 of the following: CLASI-A >= 8 and/or SLEDAI >= 6 will be enrolled in Cohort B to receive medium dose of Enpatoran. | Drug: Enpatoran medium dose<br>* Participants will receive film-coated tablets of Enpatoran at a medium dose, orally, BID up to 24 weeks.<br>* Other names: M5049;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A: Percent Change from Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI-A) at Week 16 |  | Baseline, Week 16 | 
| Cohort B: British Isles Lupus Assessment Group (BILAG)-Based Composite Lupus Assessment (BICLA) Response at Week 24 |  | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A and Cohort B: Safety Profile as Assessed by Incidence of Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs of Special Interest, Clinically Significant Abnormalities in Laboratory Parameters and QT Interval Corrected |  | Baseline (Day 1) up to End of Safety Follow-up Period (Week 33) | 
| Cohort A and Cohort B: Change from Baseline in Cutaneous Lupus Activity Investigator's Global Assessment (CLA-IGA) at Week 16 and Week 24 |  | Baseline, Week 16 and 24 | 
| Cohort A and Cohort B: Change from Baseline in Physician's Global Assessment of Cutaneous Lupus Disease Activity at Week 16 and 24 |  | Baseline, Week 16 and 24 | 
| Cohort B: Participants with British Isles Lupus Assessment Group (BILAG)-Based Composite Lupus Assessment (BICLA) Response and with Clinically Meaningful Corticosteroids (CS) Reduction | CS reduction is defined as the reduction of daily prednisone-equivalent dose from >= 10 mg at Day 1 to <= 5 mg by the Week 12 visit and sustained through Week 24. | Day 1 up to Week 24 | 
| Cohort A: Clinically Meaningful Corticosteroids (CS) Reduction | CS reduction is defined as the reduction of daily prednisone-equivalent dose from >= 10 mg at Day 1 to <= 5 mg by the Week 12 visit and sustained through Week 24. | Day 1 up to Week 24 | 
| Cohort A: Ocurrence of Cutaneous Lupus Activity Investigator's Global Assessment (CLA-IGA) Score 0 or 1 at Week 16 and Week 24 |  | At Week 16 and 24 | 
| Cohort B: Systemic lupus Erythematosus Responder Index-4 (SRI-4) Response at Week 24 |  | At Week 24 | 
| Cohort B: Lupus Low Disease Activity State (LLDAS) Attainment at Week 24 |  | At Week 24 | 
| Cohort B: Remission Attainment at Week 24 |  | At Week 24 | 
| Cohort B: Change From Baseline in Tender Joint Count and Swollen Joint Count at Week 24 |  | Baseline, Week 24 | 
| Cohort B: Change from Baseline in Physician's Global Assessment at Week 24 |  | Baseline, Week 24 | 
| Cohort B: Time to First Moderate/Severe British Isles Lupus Assessment Group (BILAG) Flare |  | Day 1 through Week 24 | 
| Cohort B: Time to First Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index (SFI) Severe Flare |  | Day 1 through Week 24 | 
| Cohort A and B: Change from Baseline in Skindex 29+3 Symptom Domain Score at Week 24 |  | Baseline, Week 24 | 
| Cohort A and B: Change from Baseline in the Skindex 29+3 Functioning and Emotion Domain Scores at Week 24 |  | Baseline, Week 24 | 
| Change from Baseline in the Skindex 29+3 Lupus-Specific Domain Score at Week 24 |  | Baseline, Week 24 | 
| Cohort A and B: Change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scores at Week 24 |  | Baseline, Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Toll-like Receptor 7, Toll-like Receptor 8, WILLOW, Adults, SLE, CLE, Lupus, Discoid lupus erythematosus, Subacute cutaneous lupus erythematosus, M5049, Enpatoran