Overview

Background

People with systemic lupus erythematosus (SLE) are at risk of developing complications in their blood vessels. This can increase the risk of heart attacks or stroke. No medications have been effective at reducing this risk in people with lupus.

Objective

To test whether a drug (anifrolumab) can improve blood vessel function and reduce blood vessel inflammation in people with SLE.

Eligibility

People aged 18 to 80 years with SLE.

Design

Participants will undergo screening. They will have a physical exam. They will have blood and urine tests. They will have a test of their heart function and a chest X-ray. They will answer questions about their SLE symptoms.

Participants will visit the clinic 9 times in 8 months. After screening, visits will be 4 weeks apart. Each visit may take up to 4 hours.

Participants will receive infusions from a tube attached to a needle inserted into a vein in the arm (IV). Some will receive anifrolumab. Others will receive a placebo treatment. They will not know which one they are getting.

At some visits they will have additional tests:

CAVI (cardio-ankle vascular index) tests blood vessel function. Participants will lie still for 20 minutes. Small electrodes will be placed on both wrists with stickers. A microphone will be placed on their chest. Blood pressure cuffs will be wrapped around their ankles and arms.

FDG-PET/CT is an imaging procedure. Participants will receive a substance through an IV line. They will lie on a table for 110 minutes while a machine captures images of their body.

Eligibility

• INCLUSION CRITERIA:

        In order to be eligible to participate in this study, an individual must meet all of the
        following criteria:
          1. Provision of signed and dated informed consent form
          2. Stated willingness to comply with all study procedures and availability for the
             duration of the study
          3. Male or female, aged 18-80 years
          4. In good general health as evidenced by medical history or diagnosed with SLE diagnosed
             per American College of Rheumatology 1997 revised SLE classification criteria.
          5. Prednisone < or equal to 10 mg/day for at least 2 weeks before screening and
             maintained throughout randomization (day 1)
          6. Stable standard of care lupus therapies for at least 4 weeks before screening and
             maintained through randomization (day 1)
          7. Abnormal cardio-ankle vascular index(CAVI) at screening OR up to 90 days prior to the
             screening visit (based on 2 SD above median of healthy controls based on historical
             data from our own patient cohorts 8. Stable medications for diabetes, hypertension
             and/or statins for at least the previous 3 months. No changes of these medications or
             immunosuppressive drugs will be allowed during trial.
        9. For females and males of reproductive potential: use of highly effective contraception
        from screening and agreement to use such a method during study participation and for an
        additional 16 weeks after the end of study medication administration. For the purpose of
        this study abstinence will be considered as an effective form of contraception.
        10. Subjects must have evidence of vaccination against COVID-19 and Varicella Zoster such
        as vaccine records, or detectable antibodies in serum.
        EXCLUSION CRITERIA:
        An individual who meets any of the following criteria will be excluded from participation
        in this study:
          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. Major surgery within 8 weeks before signing the ICF or elective major surgery planned
             during the study period.
          4. Any of the following found at Screening:
               -  Aspartate aminotransferase (AST) >2.5 X upper limit of normal (ULN).
               -  Alanine aminotransferase (ALT) >2.0 X ULN.
               -  Total bilirubin >ULN (unless due to Gilbert's syndrome)
               -  Serum creatinine >2.5 mg/dL (or >181 micromol/L)
               -  Urine protein/creatinine ratio >2.0 mg/mg (or >226.30 mg/mmol)
               -  Neutrophil count <1000/microL (or <1.0 X 109/L)
               -  Platelet count <25000/microL (or <25 X 109/L)
               -  Hemoglobin <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 hemolytic anemia
               -  Glycosylated hemoglobin (HbA1c) >8% (or >0.08) at screening (diabetic subjects
                  only)
               -  Positive SARS-CoV-2 (PCR)
             Note: Abnormal screening test(s) which exclude the patient may be repeated once within
             4 weeks of the Screening Visit. If the repeat test(s) does not meet the above
             criteria, then the patient may be included in the study and will not be considered a
             screen failure.
          5. Receipt of any of the following:
               1. Azathioprine >200 mg/day
               2. Mycophenolate mofetil > 3 g/day or mycophenolic acid >2.16 g/day
               3. Oral, SC, or intramuscular methotrexate >25 mg/week
               4. Mizoribine >150 mg/day. Leflunomide more than 20 mg and any other
                  immunosuppressant usage at the discretion of the PI.
          6. Receipt of any investigational product (small molecule or biologic agent) within 4
             weeks or 5 half-lives prior to week 0 (day 1), whichever is greater.
          7. Prior receipt of anifrolumab.
          8. Receipt of any commercially available biologic agent within 5 half-lives prior to
             signing of the ICF
          9. Receipt of B cell depleting therapy (including but not limited to belimumab,
             ocrelizumab, ofatumumab, atacicept, Obinutuzumab, or rituximab), <26 weeks prior to
             the signing of the consent for all B-cell depleting therapy or <40 weeks prior to the
             signing of the ICF for atacicept.
         10. Receipt of any of the following: (a) Intra-articular, intramuscular or IV
             corticosteroids within 4 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)
         11. Receipt of the following medications during the study period will lead to immediate
             discontinuation of investigational product:
               -  Cyclophosphamide
               -  IFN therapy (alpha 2a and 2b, beta 1a and 1b, and pegylated IFNs alpha 2a and 2b)
               -  Investigational agents
               -  Biologic immunomodulators (including, but not limited to, belimumab, abatacept,
                  or rituximab)
               -  Live or attenuated vaccines
               -  Plasmapheresis
               -  BCG vaccine
               -  Any immunoglobulin (Ig) therapy
               -  Intravenous corticosteroids >1 gm methylprednisolone or equivalent.
         12. History or evidence of suicidal ideation within the past 6 months; or any suicidal
             behavior within the past 12 months based on screening or at baseline.
         13. Recent cardiac or stroke event (with in the last year prior to week 0 (day 1))
         14. Active SLE disease with SLEDAI 2K >6
         15. 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:
               1. That would make the subject unable to fully understand the ICF OR
               2. Where, in the opinion of the Principal Investigator (PI), protocol specified SOC
                  is insufficient and utilization 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
         16. Active severe SLE-driven renal disease where, in the opinion of the PI, protocol
             specified standard of care (SOC) is insufficient and utilization 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.
         17. 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.
         18. Known history of a primary immunodeficiency, splenectomy, or any underlying condition
             that predisposes the subject to infection, or a positive result for human
             immunodeficiency virus (HIV) infection confirmed by central laboratory at screening.
             Subjects refusing HIV testing during the screening period will not be eligible for
             study participation.
         19. Confirmed positive test for hepatitis B serology for:
               1. Hepatitis B surface antigen (HBsAg), OR
               2. Hepatitis B core antibody (HBcAb)
               3. If positive for HBcAb we will check hepatitis B virus (HBV) DNA. If HBV DNA is
                  detected above the lower limit of quantitation (LLOQ) by at screening subject
                  will be excluded
             Note: Subjects who are only HBcAb positive at screening will be tested every month for
             HBV DNA. To remain eligible for the study, the subject s HBV DNA levels must remain
             below the LLOQ as per the central laboratory.
         20. Positive test for hepatitis C antibody along with detectable Hepatitis C viral RNA.
         21. 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)
         22. Any herpes zoster, cytomegalovirus (CMV) or Epstein-Barr virus infection that has not
             completely resolved within 12 weeks prior to signing the ICF.
         23. Any of the following:
               1. Clinically significant chronic infection (i.e., osteomyelitis, bronchiectasis,
                  etc.) within 8 weeks prior to week 0 (day1) (chronic nail infections are allowed)
               2. Any infection requiring hospitalization or treatment with IV antibiotics not
                  completed at least 4 weeks prior to week 0 (day1)
         24. Any infection requiring oral antimicrobials (including antivirals) within 2 weeks
             prior to Day 1, except if taking antivirals/antimicrobials prophylactically.
         25. History of cancer, apart from:
               1. Squamous or basal cell carcinoma of the skin treated with documented success of
                  curative therapy >=3 months prior to Week 0 (Day 1)
               2. Cervical cancer in situ treated with apparent success with curative therapy
                  (Bullet)1 year prior to Week 0 (Day 1).
         26. Pregnancy or lactation or intend to become pregnant anytime from initiation of
             Screening until completion of study.
         27. Spontaneous or induced abortion, still or live birth, or pregnancy 4 weeks prior to
             week 0 (day1)
         28. Known allergic reactions to any component of the investigational product formulation
             or history of anaphylaxis to any human gamma globulin therapy.
         29. Tested positive for COVID-19 infection on the day of screening or up to 21 days prior
             to screening.