Inclusion Criteria:
Inclusion criteria at screening:
- - Signed Informed Consent Form (ICF) 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.
- - An 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".
- - British Isles Lupus Assessment Group-2004 (BILAG) Grade B in ≥ 2 organ systems or a
BILAG Grade A in ≥ 1 organ system.
- - Physician's Global Assessment (PGA) score ≥ 1.0 on a 0 to 3 Visual Analogue Scale
(VAS).
- - Currently treated with one or more of the following SLE background medications:
- Anti-malarials (≤ 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, 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.
Inclusion criteria at randomization:
- - 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 items of serological evidence of active SLE
or biological variables predictive of Type 1 Interferon (IFN-1) high signature (in a
Screening sample as measured by central laboratory):
- Anti-dsDNA antibodies elevated to above normal,
- Complement C3 < lower limit of normal,
- Antinuclear Antibodies with a titer of at least 1:160,
- Anti-Smith antibody elevated to above normal,
- Platelets < 200 000/μL,
- Urine protein/creatinine ratio > 12.5 mg/mmol (110.5 mg/g).
- - 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 (≤ 1.44g/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 intravenous (i.v.) or ≤ 200 mg/week s.
c.).
- - WoCBP must have a negative urine pregnancy test at Randomization.
Main
Exclusion Criteria:
- - Pregnant, planning to be become pregnant up to Final Study Visit or lactating women.
- - Severe central nervous system lupus or active severe or unstable neuropsychiatric SLE
characterized by: 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 Principal Investigator, 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.
- - A diagnosis of mixed connective tissue disease or any history of overlap syndromes of
SLE with psoriasis, rheumatoid arthritis, erosive arthritis, scleroderma, autoimmune
hepatitis or uncontrolled autoimmune thyroid disease.
- - 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 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 basal or squamous
cell skin or mucosal lesions, including dysplasia and carcinoma in situ),
lymphoproliferative disease, or history of total lymphoid irradiation.
- - Presence of macular edema or active uveitis detected by optical coherence tomography
(OCT) during screening.
- - 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) at screening assessment.
- - 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, tacrolimus, sirolimus, mizoribine, etc.
- Pulse methylprednisolone.
- - Vaccination with live vaccines (including live vaccines for COVID-19).
- - Intra-articular, intramuscular or i.v. CS within 6 weeks 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.
- - 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,
within 12 months prior to Randomization.
- - Treatment with anifrolumab 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.
