Efficacy and Safety of Four Doses of Cenerimod Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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The purpose of the study is to assess the efficacy and safety of 4 doses of cenerimod versus placebo in adult subjects with systemic lupus erythematosus (SLE).

Detailed Description
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This is a Phase 2b, multicenter, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 4 doses of cenerimod versus placebo in adult subjects with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE).

Official Title
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A Phase 2b, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy, Safety, and Tolerability of Cenerimod in Subjects With Moderate to Severe Systemic Lupus Erythematosus (SLE)

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Cenerimod 0.5 mg
* Drug: Cenerimod 1 mg
* Drug: Cenerimod 2 mg
* Drug: Cenerimod 4 mg
* Drug: Placebo
* Drug: cenerimod 2 mg (ex-4 mg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form prior to any study-mandated procedure Diagnosis of SLE made at least 6 months prior to Screening, by fulfilling at least 4 of the 11 criteria for SLE as defined by the American College of Rheumatology (ACR) criteria A mSLEDAI-2K score ≥ 6 of at least 2 points for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers). Currently treated with stable doses of one or more of the following background medications: NSAIDs Anti-malarials (≤ 400 mg/day hydroxychloroquine, ≤ 500 mg/day chloroquine, ≤ 100 mg/day quinacrine) Mycophenolate mofetil (≤ 2 g/day) Mycophenolic acid (≤ 1440 mg/day) Azathioprine (≤ 2 mg/kg/day) Methotrexate (≤ 20 mg/week) Corticosteroids (≤ 40 mg/day prednisone or equivalent) Belimumab (≤10 mg/kg every 4 weeks intravenously, or 200 mg/week subcutaneously). History or presence of positive autoantibodies measured by central laboratory defined as follows: (a) Positive antinuclear antibody (ANA) test measured by immunofluorescence assay (IFA) with titre ≥1:80; AND/OR (b) positive anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibodies with titre ≥30 IU/mL Women of childbearing potential: Must have a negative serum pregnancy test at Screening Must agree to undertake monthly urine pregnancy tests during the study Must use highly effective methods of contraception from the screening visit until 6 months after taking the last dose of study treatment. Exclusion Criteria: Active lupus nephritis or a renal biopsy demonstrating immune complex mediated glomerulonephritis compatible with lupus nephritis. CNS (Central Nervous System) lupus and severe forms of vasculitis requiring systemic immunosuppressive treatment A diagnosis of mixed connective tissue disease or any history of overlap syndromes of SLE with rheumatoid arthritis, erosive arthritis, scleroderma or autoimmune hepatitis History or presence of Mobitz type II or third-degree atrioventricular block, sick sinus syndrome, symptomatic bradycardia or syncope associated with cardiac disorders Subjects who experienced myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack, vascular thrombosis, decompensated heart failure requiring hospitalization, or heart failure defined by the New York Heart Association Class III/IV within six months prior to Screening An elevated QT corrected for HR (Heart Rate) on the basis of Fridericia's formula interval of > 470 ms (females) / > 450 ms (males) History or presence of severe respiratory disease or pulmonary fibrosis Active or latent tuberculosis Ongoing bacterial, viral or fungal infection that is of clinical concern in the judgment of the investigator or history of any serious infection Subjects who have congenital or acquired severe immunodeficiency or known HIV infection or positive HIV testing Presence of macular edema or active uveitis Type 1 or 2 diabetes that is poorly controlled according to investigator judgment, or diabetes complicated with organ involvement such as diabetic nephropathy or retinopathy Significant hematology abnormality: Lymphocyte count < 800 /μL (0.8 × 10e9/L); hemoglobin < 9 g/dL; WBC (White Blood Cell) count < 2500/μL (2.5 × 10e9/L) or platelets < 75000/μL (75 × 10e9/L) Estimated glomerular filtration rate < 60 mL/min/1.73 m2 Known allergy to S1P (sphingosine-1-phosphate) receptor modulators or any of the cenerimod formulation excipients

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
Interventional Model Description: Participants randomized to the 4 mg arm who are still on treatment at month 6 will be re-randomized in a 1:1 ratio to placebo or cenerimod 2 mg to enter Treatment Period 2 and will continue study treatment for a total maximum of 12 months.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cenerimod 0.5 mg<br>Participants will receive cenerimod 0.5 mg once daily in addition to background SLE therapy. Treatment Period 1 is 6 months long. It will start with the administration of the first dose of study treatment, after randomization, and end at the Month 6 visit. All randomized participants need to complete Treatment Period 1 before continuing in Treatment Period 2. In Treatment Period 2 participants will continue with cenerimod 0.5 mg for a further 6 months and end study treatment at the Month 12 visit. | Drug: Cenerimod 0.5 mg<br>* Cenerimod will be supplied as a film-coated tablets at the dose of 0.5 mg<br>|
| Experimental: Cenerimod 1 mg<br>Participants will receive cenerimod 1 mg once daily in addition to background SLE therapy. Treatment Period 1 is 6 months long. It will start with the administration of the first dose of study treatment, after randomization, and end at the Month 6 visit. All randomized participants need to complete Treatment Period 1 before continuing in Treatment Period 2. In Treatment Period 2 participants will continue with cenerimod 1 mg for a further 6 months and end study treatment at the Month 12 visit. | Drug: Cenerimod 1 mg<br>* Cenerimod will be supplied as a film-coated tablets at the dose of 1 mg<br>|
| Experimental: Cenerimod 2 mg<br>Participants will receive cenerimod 2 mg once daily in addition to background SLE therapy. Treatment Period 1 is 6 months long. It will start with the administration of the first dose of study treatment, after randomization, and end at the Month 6 visit. All randomized participants need to complete Treatment Period 1 before continuing in Treatment Period 2. In Treatment Period 2 participants will continue with cenerimod 2 mg for a further 6 months and end study treatment at the Month 12 visit. | Drug: Cenerimod 2 mg<br>* Cenerimod will be supplied as a film-coated tablets at the dose of 2 mg<br>|
| Experimental: Cenerimod 2 mg (Ex-4mg)<br>Half the participants that complete treatment with cenerimod 4 mg in Treatment Period 1 will be re-randomized to cenerimod 2 mg once daily in addition to background SLE therapy during Treatment Period 2. Participants will receive cenerimod 2 mg for 6 months and end study treatment at the Month 12 visit. | Drug: cenerimod 2 mg (ex-4 mg)<br>* Cenerimod will be supplied as a film-coated tablets at the dose of 2 mg<br>|
| Placebo Comparator: Placebo (Ex-4mg)<br>Half the participants that complete treatment with cenerimod 4 mg in Treatment Period 1 will be re-randomized to placebo (matching cenerimod) once daily in addition to background SLE therapy during Treatment Period 2. Participants will receive cenerimod 2 mg for 6 months and end study treatment at the Month 12 visit. | Drug: Placebo<br>* Matching placebo will be supplied as identical film-coated tablets formulated with the same excipients but without the active ingredient, cenerimod<br>|
| Experimental: Cenerimod 4 mg<br>Participants will received cenerimod 4 mg once daily in addition to background SLE therapy for up to 6 months in Treatment Period 1. The participants randomized to the 4 mg treatment who were still on treatment at Month 6 were re-randomized in a 1:1 ratio to placebo or cenerimod 2 mg to enter Treatment Period 2. The participants who did not complete 6 months of cenerimod 4 mg treatment will be analyzed in the Non Re-randomized (Ex-4mg) treatment group. | Drug: Cenerimod 4 mg<br>* Cenerimod will be supplied as a film-coated tablets at the dose of 4 mg<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo (matching cenerimod) once daily in addition to background SLE therapy. Treatment Period 1 is 6 months long. It will start with the administration of the first dose of study treatment, after randomization, and end at the Month 6 visit. All randomized participants need to complete Treatment Period 1 before continuing in Treatment Period 2. In Treatment Period 2 participants will continue with placebo (matching cenerimod) for a further 6 months and end study treatment at the Month 12 visit. | Drug: Placebo<br>* Matching placebo will be supplied as identical film-coated tablets formulated with the same excipients but without the active ingredient, cenerimod<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Month 6 in the Modified Systemic Lupus Erythematosus Activity Index 2000 (mSLEDAI-2K) Score | The primary endpoint is the absolute change from baseline in the modified Systemic Lupus Erythematosus Activity Index 2000 (mSLEDAI-2K) score. The SLEDAI-2K is a cumulative index of lupus disease activity scored by the physician. It is calculated from 24 individual descriptors across 9 organ systems, with weighted scores of 2-8, and measures disease activity within the last 10 days. 0 points indicates inactive disease, and 105 points is the maximum possible score. In this study the SLEDAI-2K was modified, to exclude leucopenia (minus 1 point), due to the mechanism of action of cenerimod. Improvement in systemic lupus erythematosus disease activity is defined as a reduction in SLEDAI-2K score of greater than or equal to 4. A decreased score, i.e., a negative change, indicates an improvement in systemic lupus erythematosus disease activity from baseline to Month 6. | Baseline (Day 1) and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response on Systemic Lupus Erythematosus Responder Index 4 (SRI-4) at Month 6 as Compared to Baseline | A responder could only be assessed if the full information of all body systems was available. A participant was defined as a responder based on the Systemic Lupus Erythematosus Responder Index 4 (SRI-4) was a composite, binary endpoint based on three variables: mSLEDAI-2K score had to have a reduction from baseline greater than or equal to 4, Physician Global Assessment (PGA) had to have an increase from baseline less than or equal to 0.3. The PGA is a 100 mm visual analog scale used by the physician to assess disease activity ranging for 0 to 3. The scale is anchored with values from 0 = none and 3 = severe), and BILAG-2004 (no new BILAG A organ domain score and at most one new BILAG B organ domain score) compared with baseline. If one of the SRI-4 mSLEDAI-2K, PGA and BILAG variables were not met the subject was scored a non-responder. Participants that did not fit at least one of the above criteria were assigned to the missing group. | Baseline (Day 1) and Month 6 | 
| British Isles Lupus Assessment Group-2004 (BILAG) Disease Activity Index Response at Month 6 | The British Isles Lupus Assessment Group-2004 (BILAG) is a comprehensive tool used by the physician to assess disease activity and is sensitive to small changes over time. Response (no worsening) at Month 6 on BILAG-2004 disease activity index was defined as no new BILAG A organ domain score and no more than one new BILAG B organ domain score compared with baseline. No analysis is reported because the model did not meet the convergence criteria. | Baseline (Day 1) and Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Musculoskeletal and connective tissue disorders