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Nature of Anifrolumab Impact on Vaccine-Emergent Immunity in SLE

Recruiting
18 - 70 years of age
Both
Phase N/A

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Overview

This study to examines the impact of anifrolumab on disease activity, immune phenotypes, and development of neutralizing antibodies to quadrivalent influenza vaccine in patients with Systemic Lupus Erythematosus (SLE). 10 patients with moderately to severely active SLE will be treated with anifrolumab in addition to standard of care lupus treatments and 10 will receive only standard of care medications. All will receive influenza vaccine.

Description

This group of researchers previously observed that lupus patients with an elevated interferon alpha signal produced less neutralizing antibody to influenza vaccine which was directly or indirectly associated with increased flares and autoantibody production after immunization. Anifrolumab is an inhibitor of signaling through the Type I interferon alpha beta receptor. The current study is an open label parallel group pilot study to examine the impact of anifrolumab on development of neutralizing antibodies to quadrivalent influenza vaccine in patients with SLE. 10 patients with moderately to severely active SLE will initiate treatment with anifrolumab while continuing standard of care medications and 10 will receive only standard of care medications. Two weeks after baseline all will receive influenza vaccine. Blood samples will be drawn at baseline (Day 0), just prior to immunization (Week 2), and Weeks 4, 8, 12 and 16. Disease activity, gene/cytokine expression, autoantibody production and patient reported outcomes will also be tracked.

Eligibility

Inclusion Criteria:

  1. Provision of informed consent prior to any study specific procedures.
  2. Female and/or male aged 18 to 70 years inclusive.
  3. Meet the 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus.
  4. Have moderate to severely active signs or symptoms defined as an SLE Disease Activity Index (SLEDAI) score of at least 6 or at least one moderately to severely active manifestation scoring B or A on British Isles Lupus Assessment Group (BILAG) Index.
  5. May be taking up to 30 mg oral prednisone daily (or equivalent steroid) that has been stable for ≥ two weeks at the Baseline Visit.
  6. May be taking antimalarial treatment at any tolerated dose that has been stable for ≥ two months at the Baseline Visit.
        7, May be taking one oral or injectable standard of care immunosuppressant defined as: 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 through Day 0: (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
        8. Non steroidal anti-inflammatory drugs (NSAIDS), topical or ocular steroids, or topical
        or ocular calcineurin inhibitors are allowed with any dosing schedule (prn or fixed
        dosing).
        9. Female subjects must use 2 effective methods of avoiding pregnancy, only one of which is
        a barrier method, from the time they sign consent until 12 weeks after the last dose of
        study medication unless the subject is surgically sterile (e.g. bilateral oophorectomy or
        complete hysterectomy), has a sterile male partner, is at least 1 year postmenopausal, or
        practices sustained abstinence consistent with the subject's customary lifestyle.
        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 threshold laboratory
        value of post-menopausal at screening. Effective methods of birth control include those
        listed in Appendix 12.8. Ineffective methods that should not be used are listed in Appendix
        12.9
        10. All males (sterilized or non-sterilized) who are sexually active must use condom (with
        spermicide where commercially available for contraception) from Day 1 until at least 12
        weeks after receipt of the final dose of IP. It is strongly recommended that the female
        partner of a male subject also use an effective method of contraception from Appendix 12,8
        in the protocol (other than a barrier method) throughout this period. Male subjects must
        not donate sperm during the course of the study and for 12 weeks after the last dose of the
        investigational product.
        11. Females with an intact cervix must have documentation of a normal Pap smear with no
        documented malignancy or abnormalities (e.g., cervical intraepithelial neoplasia grade III,
        carcinoma in situ, or adenocarcinoma in situ within 2 years prior to randomization. Any
        abnormal Pap smear result documented within 2 years prior to randomization must be repeated
        to confirm patient eligibility.
        12. Meets all of the following tuberculosis criteria:
          -  No signs or symptoms of active tuberculosis prior to or during Screening.
          -  No medical history suggestive of active tuberculosis.
          -  No recent contact with a person with active tuberculosis OR if there has been such
             contact, referral to a physician specializing in tuberculosis to undergo additional
             evaluation prior to randomization (documented comprehensively in source), and, if
             warranted, receipt of appropriate treatment for latent tuberculosis at or before the
             first administration of investigational product.
          -  No history of latent tuberculosis prior to initial Screening visit, with the exception
             of latent tuberculosis with documented completion of appropriate treatment.
             13. Testing for Inclusion in the Study for those in the anifrolumab arm:
        Purified Protein Derivative or Tuberculosis spot test within 12 weeks prior to or during
        screening; if negative, subject is eligible. If positive or indeterminate, subject must
        undergo repeat test and chest x-ray. If both negative, subject is eligible.
        Coronavirus disease (COVID-19) negative polymerase chain reaction test or equivalent test
        for active infection such as rapid antigen test result during screening period and no known
        or suspected exposure within 2 weeks prior to screening. If there is a known or suspected
        exposure, a subject must be negative upon retest obtained 2 weeks after exposure and must
        remain asymptomatic for inclusion in the study.
        Exclusion Criteria:
          1. Involvement in the planning and/or conduct of the study (applies to all staff at the
             Coordinating Clinic and/or at the study site)
          2. Have already received the 2020-2021 quadrivalent influenza vaccine.
          3. Receipt of any of the following:
             Any live or attenuated vaccine within 8 weeks prior to signing the ICF. Administration
             of killed vaccines is acceptable as long as not the influenza vaccine.
             Bacillus Calmette-Guerin (BCG) vaccine within 1 year of signing the ICF
             Blood transfusion or receipt of blood products within 4 weeks prior to signing the
             informed consent form (ICF)
          4. For patients with active or ongoing nephritis there must be two proteinuria data
             points available within the last two months to confirm a stable protein/creatine ratio
             as defined by no increase of > 400 mg/gm between the first and second collection.
             There may be a delay of up to two weeks between screening and baseline for a repeat
             protein/creatinine ratio to be performed. The criteria will apply to the most recent
             two tests.
          5. In the opinion of the investigator, the patient has any active, unstable
             organ-threatening manifestations of SLE. At the investigator's discretion there may be
             a delay of up to two weeks between screening and baseline for appropriate diagnostic
             testing to confirm this criterion is not met.
          6. Lactating or pregnant females or females who intend to become pregnant or begin
             breastfeeding anytime from initiation of Screening until the end of the 12-week safety
             follow-up period following last dose of IP.
          7. Spontaneous or induced abortion, still or live birth, or pregnancy ≤4 weeks prior to
             signing the informed consent form (ICF).
          8. History of cancer, apart from:
             Squamous or basal cell carcinoma of the skin treated with documented success of
             curative therapy ≥3 months prior to Week 0 (Day 1).
             Cervical cancer in situ treated with apparent success with curative therapy ≥1 year
             prior to Week 0 (Day 1).
          9. Recent infection requiring hospitalization or use of intravenous anti-infectives
             within four weeks of signing the informed consent form or oral anti-infectives within
             two weeks of baseline or known history of splenectomy.
         10. Any elevation in liver function tests within two months prior to signing the informed
             consent or at the Screening visit will require reflex screening for active hepatitis.
             Any confirmed positive screening for hepatitis serology will be exclusionary
             including:
               1. Hepatitis B surface antigen (HBsAg), OR
               2. Hepatitis B core antibody (HBcAb) AND hepatitis B virus (HBV) DNA detected above
                  the lower limit of quantitation (LLOQ) by reflex testing by the central
                  laboratory at screening.
               3. Positive test for hepatitis C antibody as confirmed by central laboratory.
         11. Other infections:
               1. Any clinical cytomegalovirus (CMV) or Epstein-Barr virus infection that has not
                  completely resolved within 12 weeks prior to signing the ICF.
               2. Opportunistic infection requiring hospitalization or IV antimicrobial treatment
                  within 3 years of randomization.
               3. Clinically significant chronic infection (e.g., osteomyelitis, bronchiectasis,
                  etc) within 8 weeks prior to signing the informed consent form (ICF) (chronic
                  nail infections are allowed).
         12. For subjects to receive anifrolumab: any severe case of herpes zoster infection at any
             time prior to Baseline, including, but not limited to, non-cutaneous herpes (ever),
             herpes encephalitis (ever), recurrent herpes zoster (defined as 2 episodes within 2
             years) or ophthalmic herpes involving the retina (ever). Any herpes zoster infection
             that has not completely resolved within 12 weeks prior to signing the ICF. History of
             positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus
             core antibody.
         13. Liver function tests (AST/ALT) > 2.5 X upper limit of normal for the testing
             laboratory for any cause.
         14. Urine dipstick >/= 2+ with reflex protein/creatinine ratio >/= 3 gm/gm
         15. White blood cells </= 2.0 x 10,9 Hg </= 7.0 mg/dl, or platelets dropping from normal
             values to </= 100 x 109 unless stable for two assessments at least one week apart or
             any platelet counts </=40 x 109 even if stable.
         16. Known to have tested positive for human immunodeficiency virus.
         17. Any history of severe COVID-19 infection (e.g. requiring hospitalization, intensive
             care unit (ICU) care or assisted ventilation) or any prior COVID-19 infection with
             unresolved sequelae.
         18. Participation in another clinical study in which an investigational product that is
             not currently marketed was received during the last two months prior to Screening or
             for five half-lives of that study agent, whichever is longer.
         19. Currently receiving any medications restricted by this protocol within two months or
             five half-lives of the agent whichever is longer: to include any cytotoxic agent (e.g.
             cyclophosphamide) or a marketed biologic agent (e.g. belimumab, abatacept, infliximab,
             any Tumor Necrosis Factor inhibitor, or any of the agents listed in the Appendix 12.11
             of the protocol).
         20. Persistent toxicities as per Common Terminology Criteria for Adverse Events (CTCAE)
             that is > grade 2 and caused by current treatments.
         21. Hypersensitivity including anaphylaxis, known history of allergy or reaction to any
             component of the investigational product (IP) formulation or history of anaphylaxis to
             any human gamma globulin therapy (anifrolumab group only)
         22. Known history of drug or alcohol abuse considered clinically significant by the
             investigator within one year of screening
         23. Major surgery within 8 weeks before signing the informed consent form (ICF) or
             elective major surgery planned during the study period

Study details

Systemic Lupus Erythematosus (SLE)

NCT04726553

Oklahoma Medical Research Foundation

25 January 2024

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