Omalizumab for Lupus
Condition: Systemic Lupus Erthematosus; Sjogren's Syndrome
MeSH terms: Sjogren's Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

        -  Systemic Lupus Erythematosus (SLE or lupus) is an autoimmune disease, which means the
           body's immune system mistakenly attacks healthy tissue resulting in inflammation and
           tissue damage. SLE can involve almost any organ and its symptoms can range in severity
           from mild to life-threatening; symptoms also vary from person to person. Current
           treatments for lupus are not effective for some people. Medications used to treat lupus
           can have serious side effects.

        -  Omalizumab is a drug that has been used to treat severe allergic asthma. It helps to
           prevent allergic reactions by reducing some antibodies in the blood. These antibodies
           are also present in some people with Lupus. Researchers want to see if omalizumab is a
           safe and effective treatment for people with Lupus.

      Objectives:

      - To test the safety of omalizumab for people with lupus.

      Eligibility:

      - Individuals at least 18 years of age who have moderately active Lupus even with standard
      treatments.

      Design:

        -  Subject screening will take place at the NIH Clinical Center and will include a medical
           history, a physical exam, blood and urine laboratory tests, an assessment of Lupus
           disease activity. Some participants may require some additional testing. All eligible
           persons who are interested in enrolling will be asked to come back to the NIH within 2
           weeks to begin the study.

        -  The study will be conducted in three phases, with a total of 15 study visits over 38
           weeks. Two visits will be overnight hospital stays. The rest will be outpatient visits.
           During each visit the participants will be monitored by doing a physical exam,
           assessment of their lupus disease activity, review of any treatment related side
           effects, blood and urine testing.

        -  For the first phase, participants will have infusions (under their skin) of either
           omalizumab or a placebo. They will have an overnight hospital stay for the first
           infusion and then an outpatient safety monitor visit 2 weeks after. If subjects safety
           measures are good they will return in 2 weeks and receive the second dose. They will
           then get three more doses every 4 weeks which will be given during outpatient visits to
           the NIH.

        -  In the second phase, which begins at the 16th week of the study, all participants will
           receive omalizumab. This means that subjects who had been getting omalizumab will
           continue receiving it and subjects who had been receiving the placebo will now begin
           getting omalizumab. They will have an overnight hospital stay for this infusion and will
           return in 2 weeks for a safety monitor visit. If subjects safety measures are good they
           will return in 2 weeks and receive the next dose. They will then get three more doses
           every 4 weeks which will be given during outpatient visits to the NIH.

        -  The third phase will be a final series of visits which will take place at week 32 and
           week 36. During these visits subjects will have a physical exam which includes disease
           activity assessment, blood and urine tests. No medication will be given during these
           visits.

        -  All subjects will be given information, instruction and medications for possible
           allergic reactions to omalizumab.

        -  Throughout the study other tests and procedures will be performed as needed.
    

Detailed description: 
      Background:

      The immune system in systemic lupus erythematosus is characterized by abnormal activation of
      various cell types, such as T and B lymphocytes, macrophages and dendritic cells and the
      production of autoantibodies against nuclear antigens. Until recently most of the pathogenic
      autoantibodies were thought to be IgG antibodies. We have recently shown that Lyn deficient
      mice develop a lupus nephritis-like disease which is mediated by basophils activated by IgE
      autoantibodies. Moreover, SLE patients also have elevated serum self reactive IgEs, and
      activated basophils that express the lymph node homing molecule CD62L and the MHC Class II
      molecule, HLA-DR; markers that are associated with increased disease activity. Follow up
      studies confirmed an association of IgE anti-dsDNA antibodies with active SLE using a SLEDAI
      score of 4 as a cutoff (unpublished). In addition, we have also observed a strong correlation
      of IgE dsDNA antibodies with hypocomplementemia strongly suggesting that these autoantibodies
      are serologic markers of immune activation in SLE. Based on these observations we propose
      that depleting IgE (including IgE autoantibodies) may lead to improvement in SLE by reducing
      IgE-induced basophil activation.

      Omalizumab is a humanized IgG1 monoclonal antibody against human IgE. It is approved by the
      FDA for the treatment of asthma. Omalizumab was shown to effectively deplete circulating IgE
      and decrease basophil action. In this study we propose to assess the safety of omalizumab in
      moderately active lupus patients and to assess its effect on circulating IgE autoantibodies
      and basophil activation. We will also collect preliminary data about its clinical efficacy.

      Primary Objective:

      To determine if omalizumab is tolerated in patients with Systemic Lupus Erythematosus.

      Secondary Objectives:

      To determine if the use of omalizumab in a subset of SLE patients with mild to moderate
      disease and elevated IgE autoantibody levels leads to clinical efficacy.

      Study Population:

      Adults 18 years or older diagnosed with SLE attending NIAMS outpatient clinic (OP-9) as well
      as other rheumatology outpatient clinics and private rheumatologist offices around the
      country with moderately active lupus (SLEDAI 2K score between 4-14).

      Design:

        -  Active lupus: Assess study eligibility (week -2).

        -  If fulfills the criteria randomize at 2:1 ratio of omalizumab vs. placebo respectively
           within 2 weeks (week 0).

        -  Omalizumab loading dose (600 mg) or placebo by subcutaneous injection on day 0, followed
           by omalizumab (300 mg) or placebo by subcutaneous injection every 4 weeks (weeks 4, 8,
           12)

        -  Evaluate patients at weeks 2, 4, 8, 12 and 16. Preliminary analysis of the available
           data will be done when the last subject completed the blinded phase (week 16).

        -  Open label phase: On week 16 subjects who were randomized to the placebo arm originally
           will receive 600 mg omalizumab by subcutaneous injection whereas those in the omalizumab
           arm will receive 300 mg omalizumab by subcutaneous injection in a blinded fashion. After
           that all subjects will receive omalizumab 300 mg by subcutaneous injection every 4
           weeks, on weeks 20, 24, 28.

        -  Evaluate patients at weeks 18, 20, 24, 28

        -  Follow up phase: Subjects will have a follow up evaluation 4 and 8 weeks after the last
           dose (weeks 32 and 36).

        -  Allow one time intra-muscular injection of methylprednisolone 0.4 0.75 mg/kg for
           continued disease activity/flare.

      Outcome Measures

      Primary Endpoint:

      Safety of omalizumab in patients with SLE.

      Secondary Endpoints:

      Reduced free IgE autoantibody levels: a statistical significant difference in the change in
      IgE autoantibody levels between the placebo and omalizumab groups at 16 weeks

      Decreased basophil activation: a statistically significant difference in the change in the
      proportion of activated basophils between the placebo and omalizumab groups at 16 weeks

      Reduced IgG autoantibody levels: a statistically significant difference in the change in IgG
      autoantibody levels between the placebo and omalizumab group at 16 weeks

      Pharmacodynamics as measured by total and free IgE and FcepsilonR levels with associated PK

      Clinical efficacy: the difference in clinical responders at 16 weeks.

      Clinical response will be defined as an improvement in SLEDAI 2K scores of 4 or more without
      a worsening in PGA (physician s global assessment)

      This study will provide important preliminary information about the safety and possible
      effect of IgE depletion in SLE patients. If omalizumab is well tolerated and shows
      preliminary evidence of efficacy, follow up studies testing its clinical usefulness are
      planned. This agent is expected to be devoid of the most common toxicities of therapies
      commonly used in the treatment of SLE, such as myelosuppression, amenorrhea and osteoporosis.
    

Intervention name(s): Omalizumab
Intervention type(s): Drug
Intervention description(s): For each subject, treatment with omalizumab will start with a loading dose of 600 mg followed by a maintenance dose of 300 mg every 4 weeks. The study drug will be administered as a subcutaneous injection. On Week 0 and Week 16 the medication or placebo will be administered to subjects via 4 subcutaneous injections; the remaining weeks 2 injections will be administered.Subjects will be given written directions on dealing with adverse reactions. They will also receive an Epi-Pen before discharge and instructions on how to use it.
Intervention MeSH terms: Omalizumab
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Safety Of Omalizumab In Patients With SLE; Systemic Lupus Erythematosus