Active Systemic Lupus Erythematosus

Primary Objective: To evaluate the effect of anifrolumab 300 mg compared to placebo on disease activity as measured by the difference in the proportion of subjects who achieve an SLE Responder Index of ≥4 (SRI[4]) at Week 52

Anifrolumab (MEDI-546) concentrate for solution for intravenous infusion

Anifrolumab (MEDI-546)

concentrate for solution for intravenous infusion

150 mg

Composite endpoint SRI(4), defined by the following
criteria:
- Reduction from baseline of ≥4 points in the
SLEDAI-2K and
- No new organ system affected as defined by 1 or
more British Isles Lupus Assessment Group
(BILAG)-2004 A or 2 or more BILAG-2004 B
items compared to baseline using BILAG-2004
and
- No worsening from baseline in subjects’ lupus
disease activity defined by an increase
≥0.30 points on a 3-point Physician’s Global
Assessment (PGA) visual analogue scale (VAS)
and
- No discontinuation of investigational product or
use of restricted medications beyond the
protocol-allowed thresholda before assessment

Inclusion criteria
Subjects must meet all the following criteria:
1. Aged 18 through 70 years at the time of screening
2. Written informed consent and any locally required authorisation (eg, Health
Insurance Portability and Accountability Act [HIPAA] in the USA, Data Privacy
Directive in the EU) obtained from the subject prior to performing any
protocol-related procedures, including screening evaluations
3. Completion of all screening procedures within 30 days of signing the informed
consent form (ICF)
4. Weigh ≥40.0 kg at Screening
5. Adequate peripheral venous access
6. Diagnosis of paediatric or adult SLE with a diagnosis of SLE according to the ACR
1982 revised criteria (Tan et al, 1982) ≥24 weeks prior to signing the ICF
7. Currently receiving at least 1 of the following:
(a) A dose of oral prednisone (≤40 mg/day) for a minimum of 2 weeks prior
to signing of the ICF. The dose of oral prednisone the subject is taking
must be stable for a minimum of 2 weeks prior to Week 0 (Day 1)
(b) Any of the following medications administered for a minimum of
12 weeks prior to signing the informed consent, and at a stable dose for
a minimum of 8 weeks prior to signing the informed consent and
until Day 1:
(i) Azathioprine ≤200 mg/day
(ii) Antimalarial (eg, chloroquine, hydroxychloroquine,
quinacrine)
(iii) Mycophenolate mofetil ≤2 g/day or mycophenolic acid
≤1.44 g/day
(iv) Oral, subcutaneous (SC), or intramuscular methotrexate
≤25 mg/week
(v) Mizoribine ≤150 mg/day
8. Fulfils at least 4 of the 11 ACR modified 1982 classification criteria for SLE (see
Appendix D), at least 1 of which must be:
(a) Positive antinuclear antibody (ANA) test at screening by
immunofluorescent assay (IFA) at the central laboratory with titre
≥1:80; OR
(b) Elevated anti-dsDNA antibodies OR anti-Smith (anti-Sm) antibody at
screening as determined by the central laboratory
9. At Screening, Disease Activity Adjudication Group confirmation of:
(a) SLEDAI-2K Criteria: SLEDAI-2K score ≥6 points and “Clinical”
SLEDAI-2K score ≥4 points. The “Clinical” SLEDAI-2K is the
SLEDAI-2K assessment score without the inclusion of points
attributable to any urine or laboratory results including immunologic
measures:
(i) Includes points from the following clinical components:
arthritis, myositis, rash, alopecia, mucosal ulcers, pleurisy,
pericarditis, and vasculitis
(ii) Excludes points attributed to a fever, an SLE headache, and
organic brain syndrome
(b) BILAG-2004 Level Criteria: At least 1 of the following:
(i) BILAG-2004 level A disease in ≥1 organ system
(ii) BILAG-2004 level B disease in ≥2 organ systems
(c) Physician’s Global Assessment (PGA) score ≥1.0 on a 0 to 3 VAS at
screening
10. Negative serum β-human chorionic gonadotropin (β-hCG) test at screening (females
of childbearing potential only).
11. Females of childbearing potential must use 2 effective methods of avoiding
pregnancy from Screening until 12 weeks after the final dose of investigational
product unless the subject is surgically sterile (ie, bilateral tubal ligation, bilateral
oophorectomy, or complete hysterectomy), has a sterile male partner, is 1 year
postmenopausal, or practices abstinence. Cessation of birth control after the
12-week follow up period should be discussed with a responsible physician.
 Sustained abstinence is an acceptable practice; however, periodic
abstinence, the rhythm method, and the withdrawal method are not
acceptable methods of contraception.
 Postmenopausal is defined as at least 1 year since last menses and the
subject has an elevated follicle-stimulating hormone (FSH) level greater
than the central laboratory value of post-menopausal at screening.
12. Nonsterilised males who are sexually active with a female partner of childbearing
potential must use 2 acceptable methods of effective contraception (see above) from
Day 1 until at least 12 weeks after receipt of the final dose of investigational
product
13. Females with an intact cervix must have documentation of a Pap smear with no
documented malignancy (eg, cervical intraepithelial neoplasia grade III [CIN III],
carcinoma in situ [CIS], or adenocarcinoma in situ [AIS]) within 2 years prior to
Day 1 (see Appendix X for guidance on abnormal Pap smear results)
14. Willing to forego other forms of experimental treatment during the study
15. Meets all of the following TB criteria:
(a) No history of latent or active TB prior to Screening, with the exception
of latent TB with documented completion of appropriate treatment
(b) No signs or symptoms suggestive of active TB from 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 specialising in TB to undergo
additional evaluation prior to randomisation (documented appropriately
in source), and, if warranted, receipt of appropriate treatment for latent
TB at or before the first administration of investigational product
(d) Must meet 1 of the following criteria:
(i) Negative QuantiFERON-TB Gold [QFT-G] test result for
TB obtained from the study Central Laboratory within
3 months prior to randomisation OR
(ii) Positive QFT-G test result for TB obtained during the
Screening Period from the study Central Laboratory for
which active TB has been ruled out and appropriate
treatment for latent TB has been initiated prior to the first
investigational product administration OR
(iii) Indeterminate (confirmed on retest) QFT-G test result for
TB obtained during the Screening Period from the study
Central Laboratory with ongoing QFT-G testing for TB
according to the Study Plan
(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 12 weeks prior to signing of the informed consent
At Randomisation (Day 1):
16. Day 1 “Clinical” SLEDAI-2K score ≥4 points
17. OCS dose stable for at least 2 weeks
18. Stable SLE SOC treatment (see Section 3.3.4)
19. Women of child-bearing potential must have a negative urine pregnancy test prior
to administration of investigational product

Exclusion criteria
Any of the following would exclude the subject from participation in the study:

General exclusion criteria
1. Any condition that, in the opinion of the Investigator, would interfere with
evaluation of the investigational product or interpretation of subject safety or study
results
2. Concurrent enrolment in another clinical study with an investigational product
3. Individuals involved with the conduct of the study, their employees, or immediate
family members of such individuals
4. Lactating or pregnant females or females who intend to become pregnant anytime
from initiation of Screening until the 12-week safety follow-up period following
last dose of investigational product
5. Current alcohol, drug or chemical abuse, or a history of such abuse within 1 year
before Week 0 (Day 1)
6. Major surgery within 8 weeks before signing the ICF or elective major surgery
planned during the study period (see Appendix W)
7. Spontaneous or induced abortion, still or live birth, or pregnancy ≤4 weeks prior to
signing the ICF
8. At Screening (within 4 weeks before Week 0 [Day 1]), any of the following:
(a) Aspartate aminotransferase (AST) >2.0 × upper limit of normal (ULN).
(b) Alanine aminotransferase (ALT) >2.0 × ULN.
2015
38(121)
(c) Total bilirubin >ULN (unless due to Gilbert's syndrome)
(d) Serum creatinine >2.0 mg/dL (or >181 μmol/L)
(e) Urine protein/creatinine ratio >2.0 mg/mg (or >226.30 mg/mmol)
(f) Neutrophil count <1000/μL (or <1.0 × 109
/L)
(g) Platelet count <25000/μL (or <25 × 109
/L)
(h) Haemoglobin <8 g/dL (or <80 g/L), or <7 g/dL (or <70 g/L) if related to
subject's SLE such as in active haemolytic anaemia
(i) Glycosylated haemoglobin (HbA1c) >8% (or >0.08) at screening
(diabetic subjects only)
Note: Abnormal screening laboratory tests may be repeated ONCE on a separate sample
before subject is declared a screen failure.

Exclusion criteria related to concomitant medications
9. Receipt of any investigational product (small molecule or biologic agent) within
4 weeks or 5 half-lives prior to signing of the ICF, whichever is greater (see
Appendix U)
10. Prior receipt of anifrolumab
11. Receipt of any commercially available biologic agent within 5 half-lives (see
Appendix U) prior to signing of the ICF
12. Receipt of B cell-depleting therapy (including but not limited to, epratuzumab,
ocrelizumab, or rituximab) ≤52 weeks prior to signing the ICF or if therapy was
administered >52 weeks ago absolute B cell less than the lower limit of normal or
baseline value prior to receipt of B cell-depleting therapy (whichever is lower)
13. 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
14. Regular use of >1 NSAID within 2 weeks prior to Week 0 (Day 1); OR receipt of
fluctuating doses of a NSAID within 2 weeks prior to Week 0 (Day 1)
15. Receipt of any of the following:
(a) Intra-articular, intramuscular or IV glucocorticosteroids within 6 weeks
prior to Day 1
(b) Any live or attenuated vaccine within 8 weeks prior to signing the ICF
(administration of killed vaccines is acceptable, the Sponsor
recommends Investigators ensure all subjects are up to date on required
vaccinations, including influenza [inactivated/recombinant] vaccine
prior to study entry)
(c) Bacillus Calmette-Guerin (BCG) vaccine within 1 year of signing the
ICF
(d) Any restricted medication listed in Appendix U if the washout period is
not met
(e) Blood transfusion within 4 weeks prior to signing the ICF

Exclusion criteria related to systemic lupus erythematosus and other diseases
16. History of, or current diagnosis of, a clinically significant non SLE-related
vasculitis syndrome (see Appendix T). Vasculitis due to SLE is allowed in the study
17. History or evidence of suicidal ideation (severity of 4 [active: method and intent,
but no plan] or 5 [active: method, intent, and plan]) within the past 6 months; or any
suicidal behaviour within the past 12 months based on an assessment with the
C-SSRS at screening or at baseline
18. 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; and
mononeuritis multiplex:
(a) That would make the subject unable to fully understand the ICF OR
(b) Where, in the opinion of the Principal Investigator (PI), protocol
specified SOC is insufficient and utilisation of a more aggressive
therapeutic approach, such as adding IV cyclophosphamide and/or high
dose IV pulse corticosteroid therapy or other treatments not permitted in
the protocol, is indicated
19. Active severe SLE-driven renal disease where, in the opinion of the PI, protocol
specified SOC is insufficient and utilisation of a more aggressive therapeutic
approach, such as adding IV cyclophosphamide and/or high dose IV pulse
corticosteroid therapy or other treatments not permitted in the protocol, is indicated
20. Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or
any history of overlap syndromes of SLE or systemic sclerosis, as noted in A or B
below:
(a) An overlap syndrome of SLE with myositis or rheumatoid arthritis at
screening is permitted provided the subject also meets the criteria for the
classification as SLE; or
(b) A past history of mixed connective tissue disease, which over time has
developed into a diagnosis of SLE, is permitted provided diagnosis of
SLE has been present for at least 1 year
21. History of or current diagnosis of catastrophic or severe anti-phospholipid
syndrome within 1 year prior to signing the ICF. Antiphospholipid syndrome
adequately controlled by anticoagulant therapy for at least 3 months is acceptable.
22. 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
23. History of any non-SLE disease that has required treatment with oral or parenteral
corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to
signing the ICF

Exclusion criteria related to infection and malignancy risk factors
24. 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
25. Confirmed positive test for hepatitis B serology for:
(a) Hepatitis B surface antigen, OR
(b) Hepatitis B core antibody (HBcAb) AND hepatitis B virus (HBV) DNA
(>169 copies/mL [29 IU/mL]) detected by reflex testing by the central
laboratory at screening
Note: Subjects with HBcAb positivity at screening will be tested every 3 months for HBV
DNA. To remain eligible in the study, subject HBV DNA levels must remain ≤169 copies/mL
(29 IU/mL) as per the central laboratory.
26. Positive test for hepatitis C antibody as confirmed by central laboratory
27. Any severe herpes infection at any time prior to Week 0 (Day 1), including, but not
limited to, disseminated herpes (ever), herpes encephalitis (ever), recurrent herpes
zoster (defined as 2 episodes within 2 years) or ophthalmic herpes (ever)
28. Any herpes zoster infection that has not completely resolved within 12 weeks prior
to signing the ICF
29. Opportunistic infection requiring hospitalisation or parenteral antimicrobial
treatment within 3 years of randomisation
30. Any of the following:
(a) Clinically significant chronic infection (ie, osteomyelitis, bronchiectasis,
etc) within 8 weeks prior to signing the ICF (chronic nail infections are
allowed)
(b) Any infection requiring hospitalisation or treatment with IV
anti-infectives not completed at least 4 weeks prior to signing the ICF
31. Any infection requiring oral anti-infectives (including antivirals) within 2 weeks
prior to Day 1
32. History of cancer, apart from:
(a) Squamous or basal cell carcinoma of the skin treated with documented
success of curative therapy ≥3 months prior to Week 0 (Day 1)
(b) Cervical cancer in situ treated with apparent success with curative
therapy ≥1 year prior to Week 0 (Day 1)