Omalizumab for Lupus

Sjogren's Syndrome Clinical Trial

Official title: A Phase 1b, Randomized, Double-Blind, Placebo Controlled Study With an Open Label Extension to Evaluate the Safety and Tolerability of Omalizumab, A Humanized IgG1 Monoclonal Antibody in Patients With Lupus (STOP LUPUS)

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Sjogren's Syndrome
• Systemic Lupus Erthematosus

• NCT number: NCT01716312
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: January 8, 2014
• Completion date: August 24, 2017