A Phase 2b, Dose-ranging Study to Evaluate the Efficacy and Safety of Sifalimumab in Adults with Systemic Lupus Erythematosus

Subjects must meet all of the following criteria:
1. In the opinion of the investigator, must have adequate reading and writing abilities such that the subject can comprehend and complete the informed consent, and all protocol-related subject assessments.
2. Age 18-75 years at the time of screening.
3. Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
4. Fulfils at least 4 of the 11 American College of Rheumatology classification criteria for SLE, one of which must be:
a) Significantly positive antinuclear antibody test at screening; OR
b) Elevated anti-dsDNA or Sm antibody at screening.
5. Weight >= 40.0 kg at screening.
6. Diagnosis of pediatric or adult SLE with chronic disease activity requiring ongoing treatment or observation for >= 24 weeks (>= 168 days) prior to screening.
7. Currently receiving at least one of the following:
a) A stable dose of oral prednisone (or equivalent) <= 20 mg/day from at least 2 weeks (14 days) prior to signing of the informed consent through Day 1.
b) Any of the following medications administered at a stable dose for a minimum of 8 weeks (56 days) prior to signing of the informed consent through Day 1: azathioprine, antimalarial (eg. chloroquine, hydroxychloroquine, quinacrine), mycophenolate mofetil/ mycophenolic acid, weekly administrations of oral or sc methotrexate.
8. Prior to Day 1, External Adjudication Group confirmation of both:
(a) At screening, SLEDAI-2K score >= 6 points or *Clinical* SLEDAI-2K score >= 6 points.
(b) At least one of the following: BILAG-2004 Index level A disease in >= 1 body/organ system or BILAG-2004 Index level B disease in >= 2 body/organ systems.
9. Day 1 *Clinical* SLEDAI-2K score >= screening *Clinical* SLEDAI-2K score.
10. Physicians Global assessment >= 1.0 on a 0-3 scale at screening.
11. Females of childbearing potential must use 2 effective methods of avoiding pregnancy, have a sterile male partner, are 1 year postmenopausal, or practicing abstinence.
12. Non-sterilized males must practice two effective contraceptive measures with a female of childbearing potential from Day 1 through at least 180 days after the last dose of investigational product has been administered.
13. Females with an intact cervix must have documentation of a Pap smear with no documented malignancy (eg. CIN III and AIS) within 24 weeks (168 days) prior to Day 1.
14. Willing to abstain from other forms of experimental treatment for SLE during the study.
15. Meets all of the following tuberculosis (TB) criteria:
a) No history of latent or active TB prior to screening with the exception of latent TB within 3 years prior to screening with documented completion of appropriate treatment.
b) No signs or symptoms suggestive of active TB upon medical history or physical examination.
c) No recent contact with a person with active TB OR if there has been such contact, referral to a physician specializing in TB to undergo additional evaluation prior to randomization and, if warranted, receipt of appropriate treatment for latent TB at or before the first administration of investigational product.
d) Negative diagnostic TB test within 28 days prior to randomization (defined as a negative QuantiFERON-TB Gold for TB at screening) OR a positive diagnostic TB result (defined as a positive QuantiFERON-TB Gold blood assay for TB obtained during the screening period) for which active TB has been ruled out and for which appropriate treatment for latent TB has been initiated either at or before the first administration of investigational product OR a confirmed indeterminate QuantiFERON-TB Gold blood assay for TB obtained during the screening period with ongoing TB QuantiFERON-TB Gold testing at Day 57, Day 169, and Day 253.
e) A chest radiograph with no evidence of current active infection (eg. TB) or old active TB, malignancy, or clinically significant abnormalities (unless due to SLE) obtained during the screening period or anytime within 90 days prior to signing of the informed consent.
16. Adequate peripheral venous access.
17. Ability to complete and meet all requirements for randomization within 28 days after signing the informed consent form.

1. Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or confound interpretation of subject safety or study results.
2. Concurrent enrollment in any other clinical study with an investigational product within 4 weeks (28 days) prior to Day 1 or within 5 half-lives of the investigational product used in that clinical study, whichever is longer.
3. Employees of the clinical study site or any other individuals involved with the conduct of the study or immediate family members of such individuals.
4. Receipt of any of the following:
a) Any new oral prednisone therapy (or equivalent) or any change in current oral prednisone dose (or equivalent) anytime from 2 weeks (14 days) prior to signing of the informed consent through Day 1.
b) Any new dose or change in current dose of any of the following anytime in the 8 weeks (56 days) prior to signing of the informed consent through Day 1: azathioprine; any antimalarial (eg. chloroquine, hydroxychloroquine, quinacrine); mycophenolate mofetil/mycophenolic acid; oral methotrexate; or SC methotrexate.
5. Receipt of any of the following:
a) Azathioprine > 150 mg/day.
b) Mycophenolate mofetil/mycophenolic acid > 3.0 grams/day.
c) Oral or SC methotrexate > 20 mg/week.
d) Any change in route of administration of oral or SC methotrexate anytime within the 8 weeks (56 days) prior to signing of the informed consent.
6. Receipt of more than one dose of sifalimumab prior to screening.
7. Receipt of a biologic agent within 5 half-lives or prior to loss of PD and/or clinical effect, whichever is longer, prior to signing of the informed consent form.
8. A known history of allergy or reaction to any component of the investigational product formulation or history of anaphylaxis to any human gamma globulin therapy.
9. Receipt of more than one prescribed NSAID at an anti-inflammatory dose within 2 weeks (14 days) prior to Day 1; OR receipt of fluctuating doses of a prescribed NSAID within 2 weeks (14 days) prior to Day 1.
10. Receipt of any of the following:
a) Intra-articular, intramuscular or intravenous glucocorticoids within 6 weeks (42 days) prior to Day 1.
b) Any live or attenuated vaccine within 4 weeks (28 days) prior to signing the informed consent form (administration of killed vaccines is acceptable).
c) Oral anti-infectives (including antivirals) for active infection within 2 weeks (14 days) prior to Day 1.
d) Bacillus of Calmette and Guérin Vaccine (BCG) within 1 year of signing the informed consent form.
e) Any restricted medication listed in Appendix 3of the protocol.
11. Receipt of any of the following slow-acting immunosuppressants:
a) Etanercept <= 4 weeks (<=28 days) prior to signing the informed consent form.
b) Adalimumab, infliximab, or golimumab <= 12 weeks (<=84 days) prior to signing the informed consent form.
c) Rituximab or belimumab < 24 weeks (<=168 days) prior to signing the informed consent form.
12. Any fluctuation in hormone replacement therapy dose within 8 weeks (56 days) of signing the informed consent form.
13. Active severe or unstable neuropsychiatric SLE that would make the subject unsuitable for the study or unable to fully understand the informed consent, including but not limited to: aseptic meningitis; cerebral vasculitis; myelopathy; demyelination syndromes; acute confusional state; impaired level of consciousness; psychosis; acute stroke or stroke syndrome; cranial neuropathy; status epilepticus; cerebellar ataxia; and mononeuritis multiplex.
14. Within 8 weeks (56 days) prior to screening, active severe SLE-driven renal disease or unstable renal disease (eg. clinically significant increase in creatinine or active urinary sediment) that in the opinion of the investigator would make the subject unsuitable for this study.
15. A diagnosis (within 1 year of signing the informed consent form) of mixed connective tissue disease or any history of overlap syndromes of SLE with rheumatoid arthritis, erosive arthritis, or scleroderma.
16. History of, or current, inflammatory joint or skin disease other than SLE that in the opinion of the investigator could interfere with the inflammatory arthritis or skin assessments and confound the disease activity assessments.
17. History of asthma that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks (14 days) within the last 24 weeks (168 days) prior to randomization.
18. Known history of a primary immunodeficiency or an underlying condition such as human immunodeficiency virus (HIV) infection or splenectomy that predisposes the subject to infection.
19. Confirmed positive test for hepatitis B surface antigen (HBsAg) serology for:
a) Hepatitis B surface antigen (HBsAg).
b) Isolated Hepatitis B core (HBc) with HBV DNA detected by reflex testing by the central lab at screening or at any time for the duration of the study.
20. Confirmed positive test for hepatitis C serology by central laboratory.
21. Any serious herpes infection at any time prior to randomization, including but not limited to disseminated herpes, herpes encephalitis, or ophthalmic herpes.
22. Any herpes zoster infection that has not completely resolved within 12 weeks (84 days) prior to signing of the informed consent form.
23. Any of the following within 4 weeks (28 days) prior to signing the informed consent form.
a) Clinically significant active infection, including ongoing, and chronic infection (i.e. osteomyelitis, bronchiectasis, etc) but allowing chronic nail infections.
b) Any infection requiring hospitalization or treatment with IV anti-infectives.
24. Lactating or pregnant females or females who intend to become pregnant anytime from initiation of screening through the 180-day safety follow-up period following last dose of investigational product.
25. Current evidence of alcohol, drug or chemical abuse, or a recent history of such abuse < 1 year before randomization into the study.
26. History of cancer, apart from basal cell carcinoma or cervical cancer treated with apparent success with curative therapy >= 1 year before randomization into the study.
27. Major surgery (See Appendix 4) within 8 weeks (56 days) before signing the informed consent form or elective major surgery planned during the study period.
28. Spontaneous or induced abortion, still or live birth, or pregnancy <= 4 weeks (<= 28 days) prior to signing the informed consent form.
29. At screening (within 4 weeks [28 days] before Day 1), any of the following:
a) AST > 2.0 × upper limit of the normal range (ULN) unless, in the opinion of the investigator, it is caused by myositis (with an elevated CPK) associated with SLE.
b) ALT > 2.0 × ULN unless, in the opinion of the investigator, it is caused by myositis (with an elevated CPK) associated with SLE.
c) Total bilirubin > ULN (unless due to Gilbert*s syndrome).
d) Serum creatinine > 2.0 mg/dL.
e) Urine protein/creatinine ratio > 2.0.
f) Neutrophil count < 1,000/µL (or < 1.0 × 109/L).
g) Platelet count < 25,000/µL (or < 25 × 109/L).
h) Hemoglobin (Hgb) < 8 g/dL (or < 80 g/L).
i) Hemoglobin A1c (HbA1c) > 8% (or > 0.08) at screening (diabetic subjects only).