Proof-of-concept Randomized, Double-blind, Phase IIa Study to Show Feasibility, Validate Assays and Approaches, and Explore Dosing and Safety of Belimumab in Pulmonary Emphysema Patients
Overview
- Phase
- Phase 2
- Intervention
- Belimumab
- Conditions
- Chronic Obstructive Pulmonary Disease
- Sponsor
- University of Alabama at Birmingham
- Enrollment
- 17
- Locations
- 1
- Primary Endpoint
- Percent Change of Circulating Anti-GRP78 IgG Levels
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief 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.
Detailed 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.
Investigators
Mark Dransfield, MD
Principal Investigator
University of Alabama at Birmingham
Eligibility Criteria
Inclusion Criteria
- •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.
- •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.
- •Ability and willingness to give informed consent.
- •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.
- •Age 40-75 y.o. COPD is a disease of older individuals.
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).
Arms & Interventions
Belimumab
Subjects randomized to the experimental treatment arm will receive i.v. administrations of belimumab (10 mg/kg), consisting of three "loading" doses, two weeks apart, followed by five (5) more monthly infusions. The final assessment will be performed at month 8.
Intervention: Belimumab
Placebo
These subjects will be treated with identically appearing placebo i.v. on the same schedule as the experimental arm subjects (i.e., three "loading" doses, two weeks apart, followed by five more monthly infusions. Again, the final assessment will be performed at month 7 (210+10 days after treatment start).
Intervention: Placebo
Outcomes
Primary Outcomes
Percent Change of Circulating Anti-GRP78 IgG Levels
Time Frame: Plasma concentrations of the anti-GRP78 autoantibodies will be measured pre-treatment and at end of treatment at 210 days (or when subject withdraws)
Anti-GRP78 IgG is a clinically relevant surrogate biomarker of autoimmunity in pulmonary emphysema patients who have clinically relevant (and quantifiable) autoimmune responses
Secondary Outcomes
- Percent Change of Pneumococcal Polysaccharide-binding Antibodies(Prior to treatment and at end of treatment on day 210 (or the conclusion of treatment if subject withdraws))
- Percent Change of Circulating B-cells(Prior to treatment, and at treatment end on day 210 or when subject participation is terminated)
- Adverse Events(Study start to completion (7 months))