Phase 3 Study on the Efficacy and Safety of Cenerimod in Adults with Moderate-to-Severe Systemic Lupus Erythematosus

Trial ID: 2024-515870-28-00
Protocol: ID-064A301
Sponsor: Viatris Innovation GmbH

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Diseases & Conditions

Systemic lupus erythematosus

Objectives

The primary objective of this study is to evaluate the **effectiveness** of cenerimod 4 mg in reducing disease activity in patients with moderate to severe systemic lupus erythematosus (SLE) compared to placebo. This is clinically relevant as SLE is a chronic autoimmune disease characterized by periods of increased disease activity, which can lead to significant morbidity. Effective management of disease activity is crucial for improving patient outcomes and quality of life.

Secondary objectives include:

Evaluating the effect of cenerimod 4 mg on controlling the disease compared to placebo.

Participants

The clinical trial involves a total of **320 participants** diagnosed with **moderate to severe systemic lupus erythematosus**. The study population includes both male and female subjects, with an age range that encompasses both adults and adolescents. Participants were selected based on specific criteria, including a confirmed diagnosis of systemic lupus erythematosus made at least six months prior to screening, and a modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) score of 6 or higher. The trial population includes individuals currently undergoing treatment with one or more SLE background medications, such as antimalarials, mycophenolate mofetil, azathioprine, methotrexate, oral corticosteroids, or belimumab. Lifestyle considerations, such as diet and physical activity, are not specified. The trial also includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants. The selection process ensures that participants meet the necessary health criteria to evaluate the effectiveness of cenerimod 4 mg in reducing disease activity compared to placebo.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy, safety, and tolerability of **cenerimod** in adult subjects with moderate-to-severe **systemic lupus erythematosus** (SLE). This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The trial aims to assess the effectiveness of a 4 mg dose of cenerimod in reducing disease activity compared to a placebo. The study is expected to last until May 2027, with recruitment having commenced in June 2023.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as a diagnosis of SLE made at least six months prior and a modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) score of 6 or higher. Randomization will follow, contingent upon meeting additional criteria, including a clinical mSLEDAI-2K score of 4 or higher and the presence of serological evidence of active SLE. The primary endpoint is the response on the Systemic Lupus Erythematosus Responder Index (SRI-4) at Month 12 compared to baseline, with secondary endpoints including the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response and time to first confirmation of a sustained mSLEDAI-2K response.

Participants will be involved in the study for a maximum of 12 months, with regular follow-up visits to monitor their condition and treatment response. The end-of-study visit will conclude their participation, during which final assessments will be conducted. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The trial is structured to ensure rigorous assessment of cenerimod's impact on SLE, with a focus on maintaining participant safety and data integrity throughout the study duration.

Treatment

The clinical trial involves the administration of **cenerimod**, an investigational medication, in the form of a **film-coated tablet**. Cenerimod is chemically synthesized and is provided by Idorsia Pharmaceuticals Ltd. The dosage for cenerimod is set at 4 mg per day, administered orally. The maximum treatment period for participants receiving cenerimod is 12 weeks. The primary objective of the trial is to evaluate the efficacy of cenerimod in reducing disease activity in adult subjects with moderate-to-severe systemic lupus erythematosus (SLE) when used in conjunction with background therapy. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen.

In addition to cenerimod, the study includes a **placebo** group, which receives a cenerimod matching placebo. The placebo is designed to mimic the appearance of the cenerimod film-coated tablet but does not contain any active pharmaceutical ingredients. The placebo is administered orally with the same frequency and duration as the cenerimod treatment, serving as a comparator to assess the efficacy and safety of the investigational drug. The use of a placebo control is integral to maintaining the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias in the evaluation of outcomes.

Efficacy

The efficacy of cenerimod in the treatment of moderate-to-severe **Systemic Lupus Erythematosus (SLE)** will be assessed through a series of predefined endpoints in a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The primary endpoint for evaluating efficacy is the response on the Systemic Lupus Erythematosus Responder Index (SRI-4) at Month 12 compared to baseline. Secondary endpoints include the response on the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) at Month 12 compared to baseline, the time to first confirmation of a 4-month sustained mSLEDAI-2K response, and the time to first confirmation of a 4-month sustained response in mucocutaneous manifestations.

These efficacy parameters will be measured and collected at specified timepoints, with the primary and secondary endpoints being assessed at Month 12. The study will utilize validated scales such as the SRI-4 and BICLA to ensure accurate and reliable measurement of disease activity and response. The analysis will focus on comparing the efficacy of cenerimod 4 mg to placebo in reducing disease activity in adult subjects with SLE, while subjects continue their background therapy. The trial is designed to provide robust data on the effectiveness of cenerimod in this patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Screening criteria: • Signed Informed Consent Form prior to any study-mandated procedure. • Diagnosis of Systemic Lupus Erythematosus (SLE) made at least 6 months prior to Screening, according to 2019 European League Against Rheumatism / American College of Rheumatology Criteria. • A modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) score ≥ 6 and clinical mSLEDAI-2K score ≥ 4 with at least 2 points for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers). The mSLEDAI-2K score does not include "leukopenia". • Currently treated with one or more of the following SLE background medications: - Antimalarials (≤ 400 mg/day hydroxychloroquine, ≤ 500 mg/day chloroquine, ≤ 100 mg/day quinacrine). - Mycophenolate mofetil (≤ 2 g/day) / mycophenolic acid (≤1.44 g/day). - Azathioprine (≤ 2 mg/kg/day). - Methotrexate (≤ 25 mg/week). - Oral Corticosteroids (OCS): if OCS is the only SLE background medication, ≥ 7.5 mg/day and ≤ 30 mg/day prednisone or equivalent; if OCS is not the only SLE background medication, ≤ 30 mg/day prednisone or equivalent. - Belimumab (≤10 mg/kg every 4 weeks intravenously [i.v.], or 200 mg/week subcutaneously [s.c.]). • Treatment with antimalarials, mycophenolate mofetil, mycophenolic acid, azathioprine, methotrexate or belimumab must have been started at least 90 days prior to Screening. • Treatment with OCS must have been started at least 30 days prior to Screening. • For women of childbearing potential (WoCBP): - Negative serum pregnancy test at Screening. - Agreement to undertake monthly urine pregnancy tests from Randomization up to 6 months after study treatment discontinuation. - Agreement to use a highly effective method of contraception from Screening (Visit 1) up to 6 months after study treatment discontinuation.
Randomization criteria: • A clinical mSLEDAI-2K score ≥ 4 with at least 2 points for musculoskeletal or mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers). • British Isles Lupus Assessment Group-2004 (BILAG) Grade B in 2 or more organ systems or a BILAG Grade A in 1 or more organ system. • Physician's Global Assessment (PGA) score ≥ 1.0 on a 0 to 3 visual analog scale. • Presence of at least one of the following biomarkers of serological evidence of active SLE (in a Screening sample as measured by central laboratory): - Anti-dsDNA antibodies elevated above normal, - Antinuclear antibodies with a titer of at least 1:160, - Anti-Smith antibody elevated above normal. • Currently treated with one or more of the following SLE background medications that must be stable for at least 30 days prior to Randomization (except OCS, which must be stable for at least 15 days prior to Randomization): - Antimalarials (≤ 400 mg/day hydroxychloroquine, ≤ 500 mg/day chloroquine, ≤ 100 mg/day quinacrine); - Mycophenolate mofetil (≤ 2 g/day) / mycophenolic acid (≤ 1.44 g/day); - Azathioprine (≤ 2 mg/kg/day); - Methotrexate (≤ 25 mg/week); - OCS: if OCS is the only SLE background medication, ≥ 7.5 mg/day and ≤ 30 mg/day prednisone or equivalent; if OCS is not the only SLE background medication: ≤ 30 mg/day prednisone or equivalent). - Belimumab (≤ 10 mg/kg every 4 weeks i.v. or ≤ 200 mg/week s.c.). • WoCBP must have a negative urine pregnancy test at Randomization.

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Exclusion Criteria

Pregnant, planning to become pregnant up to Final Study Visit, or lactating women.
Severe active central nervous system lupus or active severe or unstable neuropsychiatric SLE including but not limited to: aseptic meningitis; cerebral vasculitis; myelopathy; demyelination syndromes (ascending, transverse, acute inflammatory demyelinating polyradiculopathy); acute confusional state; impaired level of consciousness; psychosis; acute stroke or stroke syndrome; cranial neuropathy; status epilepticus; cerebellar ataxia; or mononeuritis multiplex: - That would make the subject unable to fully understand the ICF; OR - Where, in the opinion of the investigator/delegate, protocol-specified standard of care is insufficient and the use of a more aggressive therapeutic approach, such as adding i.v. cyclophosphamide and/or high dose i.v. pulse corticosteroid (CS) therapy or other treatments not permitted in the protocol is indicated.
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 6 months prior to Screening. • Resting Heart Rate 50 bpm as measured by the 12-lead ECG at Screening or at Randomization. • An elevated QT interval corrected according to Fridericia's formula (QTcF) interval of > 470 ms (females) / > 450 ms (males) at Screening or at Randomization.
History or presence of severe respiratory disease or pulmonary fibrosis, based on medical history, lung function, and chest X-ray (or CT scan as per local guidelines), performed at Screening or within 6 months prior to Screening. • History of clinically relevant bronchial asthma or chronic obstructive pulmonary disease that has required treatment with oral or parenteral CS for more than a total of 2 weeks within the last 6 months prior to Screening.
History or presence of malignancy (except for surgically excised and non-recurrent cutaneous basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma), lymphoproliferative disease, or history of total lymphoid irradiation within 10 years prior to Screening. • Presence of any of the following abnormalities detected during the ophthalmological evaluation and/or by optical coherence tomography (OCT) during screening: - Macular edema of any cause: diabetic, cystoid, tractional. - Foveal degeneration, macular hole, macular pseudohole, hereditary or degenerative maculopathies. - Active uveitis, papilledema. - Retinal neovascularization of any cause and in any location.• History of chronic liver or biliary disease (other than Gilbert's Syndrome) or subjects with alanine aminotransferase or aspartate aminotransferase > 3 × Upper Limit of Normal (ULN) or total bilirubin > 1.5 × ULN (unless in the context of known Gilbert's Syndrome). • Significant hematology abnormality at screening assessment: - lymphocyte count < 500/μL (0.5 × 10^9/L); - hemoglobin < 7 g/dL; - white blood cell count < 2000/μL (2.0 × 10^9/L); or - platelets 25000/μL < (25 × 10^9/L). • Estimated glomerular filtration rate < 15 mL/min/1.73 m^2.
Treatment with the following medications within 15 days or 5 half-lives of the medication (whichever is longer) prior to Randomization: - β-blockers, diltiazem, verapamil, digoxin, digitoxin, or any other antiarrhythmic or heart-rate - lowering systemic therapy. - QT-prolonging drugs with known risk of torsade de pointes irrespective of indication. • Treatment with the following medications within 30 days or 5 half-lives of the medication (whichever is longer) prior to Randomization: - Cyclophosphamide, cyclosporine, voclosporin, tacrolimus, sirolimus, etc. - Pulse methylprednisolone. - Vaccination with live vaccines. • Intra-articular, intramuscular or i.v. CS within 6 weeks prior to Randomization. • Treatment with anifrolumab within 6 months prior to Randomization. • Treatment with the following medications within 90 days or 5 half-lives of the medication (whichever is longer) prior to Randomization: - Leflunomide. - i.v. immunoglobulins. • Treatment with any investigational agent within 90 days or 5 half-lives of the drug (whichever is longer) prior to Randomization. • Treatment with B cell-depleting biological agents (e.g., rituximab or ocrelizumab) or biological immunosuppressive agents (e.g., anti-tumor necrosis factor [TNF], anti-interleukin [IL]-1, anti-IL6 therapies), within 12 months prior to Randomization. • Treatment with any of the following medications any time prior to Screening: - Alemtuzumab; - Sphingosine-1-phosphate receptor modulators (e.g., fingolimod). - Subjects previously randomized to cenerimod or placebo in any trial involving cenerimod.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	08 Jun 2023	33
France	Not Recruiting	08 Jun 2023	9
Greece	Not Recruiting	08 Jun 2023	14
Poland	Not Recruiting	08 Jun 2023	27
Romania	Not Recruiting	08 Jun 2023	17