Belimumab Treatment of Emphysema Patients With Anti-GRP78 Autoantibodies
Condition: Chronic Obstructive Pulmonary Disease; Emphysema
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Emphysema
Intervention: Belimumab; Placebo
Intervention description: Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.; An identically appearing placebo infusion.
Intervention MeSH terms: Belimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients will be randomly assigned to receive active:placebo in a ratio of 2:1.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double-blinded placebo controlled randomized clinical trial
Enrollment: 17.0
Sex: All
Minimum age: 40 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: COPD; belimumab; biologic agent; GRP78

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. A history of past tobacco smoking (>10 pack years), but quit for >6 months at the time
             of enrollment. Smoking cessation will be confirmed by serum cotinine assays.

          2. Pulmonary emphysema per chest CT scans (F950>5%). About 60% of COPD patients followed
             in the LHC registry meet these criteria.6 Chest CTs are routine, standard of practice
             evaluations for patients with COPD, so no new radiographic studies will be necessary
             for this project.

          3. Ability and willingness to give informed consent.

          4. Plasma anti-GRP78 binding IgG >mean values in former smokers with no lung disease
             (standardized OD >0.390) (hence this is a "personalized medicine" approach). Of the
             330 emphysema subjects assayed for anti-GRP78 to date, 111 (67%) met this criterion.

          5. Age 40-75 y.o. COPD is a disease of older individuals.

        Exclusion Criteria:

          1. 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.

          2. Oral steroids or cellular immunosuppressant use (e.g., cyclophosphamide) within 6
             months.

          3. History or clinical or laboratory evidence of other autoimmune syndromes.

          4. Inability or unwillingness to complete the treatment and surveillance protocols.

          5. 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).

          6. History of malignant neoplasm within the last 5 years.

          7. 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.

          8. History of a primary immunodeficiency.

          9. Significant IgG deficiency (IgG level < 400 mg/dL).

         10. Have an IgA deficiency (IgA level < 10 mg/dL).

         11. Currently on any suppressive therapy for a chronic infection (such as tuberculosis,
             pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster or atypical
             mycobacteria).

         12. Hospitalization for treatment of infection within 60 days of Day 0.

         13. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or
             anti parasitic agents) within 60 days of Day 0.

         14. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or
             dependence within 365 days prior to Day 0.

         15. History of a positive HIV test or positive screening test for HIV.

         16. Serologic evidence of current or past Hepatitis B (HB) or Hepatitis C (HC) infection
             based on positive tests for HBsAg or HBcAb, or HCAb.

         17. History of an anaphylactic reaction to parenteral administration of contrast agents,
             human or murine proteins or monoclonal antibodies.

         18. Any other clinically significant abnormal laboratory value in the opinion of the
             investigator.

         19. Any intercurrent significant medical or psychiatric illness that the investigator
             considers would make the candidate unsuitable for the study.

         20. 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:

               -  Oral contraceptive, either combined or progestogen alone

               -  Injectable progestogen

               -  Implants of levonorgestrel or etonogestrel

               -  Estrogenic vaginal ring

               -  Percutaneous contraceptive patches

               -  Intrauterine device (IUD) or intrauterine system (IUS) with <1% failure rate as
                  stated in the product label

               -  Male partner sterilization (vasectomy with documentation of azoospermia) prior to
                  the female subject's entry into the study, and this male is the sole partner for
                  that subject. For this definition, "documented" refers to the outcome of the
                  investigator's/designee's medical examination of the subject or review of the
                  subject's medical history for study eligibility, as obtained via a verbal
                  interview with the subject or from the subject's medical records

               -  Double barrier method: condom and occlusive cap (diaphragm or cervical/vault
                  caps) plus spermicidal agent (foam/gel/film/cream/suppository)

         21. Use of Excluded Medications:

               -  Anti-B-cell therapy:

                    -  Wash out of 5 therapeutic half lives after prior B-cell therapy, or until
                       pharmacodynamic effect would be minimal (e.g., 1 year following rituximab)

               -  365 days Prior to Belimumab:

                    -  Any biologic investigational agent (e.g., abetimus sodium, anti CD40L
                       antibody, BG9588/ IDEC 131)

               -  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)

                    -  Any non-biologic investigational agent

               -  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