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This is intended to be an initial "proof-of-concept" study to show feasibility, validate assays and approaches, and explore dosing and safety of belimumab in pulmonary emphysema patients who have clinically relevant (and quantifiable) autoimmune responses. The primary goal is to determine effects of belimumab on levels of autoantibodies against glucose regulated protein 78 (GRP78) among patients with pulmonary emphysema attributable to cigarette smoking. The investigators hypothesize that belimumab treatment will safely reduce circulating levels of autoantibodies that are associated with emphysema, and comorbidities of this lung disease, including atherosclerosis.
Full description
Specific Aim 1: To conduct a double-blind, Phase IIa trial, in which 18 former smokers with pulmonary emphysema (per chest CT scans), and circulating anti-GRP78 autoantibody levels >mean normal values (by ELISA), will be randomized 2:1 to belimumab vs. placebo. Subjects will receive 8 infusions of either belimumab or placebo over a 6 month interval. Plasma anti-GRP78 will be measured pre-treatment, and at 1, 3, 5, and 7 months. The investigators hypothesize belimumab therapy will more effectively reduce anti-GRP78 IgG autoantibodies, the primary endpoint of this trial, compared to placebo.
Specific Aim 2: To determine effects of the belimumab therapy on secondary endpoints (at the times detailed for Aim 1) that include levels of pneumococcal-binding antibodies (by ELISA), circulating B-cell numbers and phenotypes (by flow cytometry), and the rate and severity of adverse events (AE) at any time during treatment. The investigators hypothesize belimumab will have dose-related effects on B-cell numbers and their differentiation, while minimally reducing host defense antibodies, and will also have an acceptable AE profile.
Enrollment
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Inclusion criteria
Exclusion criteria
History of prior acute COPD exacerbations or no more than one moderate exacerbation in the last year and no exacerbations four months prior to enrollment. A past history of an acute exacerbation is the single biggest risk for recurrence.36 Exclusion of these higher-risk subjects will minimize drop-outs.
Oral steroids or cellular immunosuppressant use (e.g., cyclophosphamide) within 6 months.
History or clinical or laboratory evidence of other autoimmune syndromes.
Inability or unwillingness to complete the treatment and surveillance protocols.
Eligible for lung transplant at time of enrollment. This exclusion will mitigate any potential, however slight, that a patient could be rejected for transplantation due to surgeon concerns about this novel therapy (and will also obviate early drop-outs due to transplantation).
History of malignant neoplasm within the last 5 years.
Evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or those, in the investigator's judgment, pose a significant suicide risk.
History of a primary immunodeficiency.
Significant IgG deficiency (IgG level < 400 mg/dL).
Have an IgA deficiency (IgA level < 10 mg/dL).
Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster or atypical mycobacteria).
Hospitalization for treatment of infection within 60 days of Day 0.
Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 60 days of Day 0.
Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 365 days prior to Day 0.
History of a positive HIV test or positive screening test for HIV.
Serologic evidence of current or past Hepatitis B (HB) or Hepatitis C (HC) infection based on positive tests for HBsAg or HBcAb, or HCAb.
History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies.
Any other clinically significant abnormal laboratory value in the opinion of the investigator.
Any intercurrent significant medical or psychiatric illness that the investigator considers would make the candidate unsuitable for the study.
Women of Child Bearing Potential (WCBP) must have a negative serum pregnancy test (either blood or urine) at screening, and agree to 1 of the following:
Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 16 weeks after the last dose of study agent (Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception)
OR
Consistent and correct use of 1 of the following acceptable methods of birth control for 1 month prior to the start of the study agent, during the study, and 16 weeks after the last dose of study agent:
Use of Excluded Medications:
Anti-B-cell therapy:
365 days Prior to Belimumab:
Investigational agent applies to any drug not approved for sale in the country in which it is being used
30 Days Prior to Belimumab (or 5 half lives, whichever is greater)
Investigational agent applies to any drug not approved for sale in the country in which it is being use
Live vaccines within 30 days prior to baseline or concurrently with belimumab
Primary purpose
Allocation
Interventional model
Masking
17 participants in 2 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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