Chronic Obstructive Pulmonary Disease, Emphysema
Conditions
Keywords
COPD, belimumab, biologic agent, GRP78
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.
Interventions
BIOLOGICALBelimumab
Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.
DRUGPlacebo
An identically appearing placebo infusion.
Sponsors
GlaxoSmithKline
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blinded placebo controlled randomized clinical trial
Intervention model description
Patients will be randomly assigned to receive active:placebo in a ratio of 2:1.
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change of Circulating Anti-GRP78 IgG Levels | 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | Treatment effects on concentrations of pneumococcal polysaccharide-binding antibodies by ELISA |
| Percent Change of Circulating B-cells | Prior to treatment, and at treatment end on day 210 or when subject participation is terminated | Treatment effect on relative percentages of circulating B-cells (CD20+) by flow cytometry |
| Adverse Events | Study start to completion (7 months) | Adverse events will be evaluated according to criteria outlined in the National Cancer Institure (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Belimumab: Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion. | 11 |
| 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).
Placebo: An identically appearing placebo infusion. | 6 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Specific Aim 1 | Physician Decision | 1 | 0 |
| Specific Aim 2 | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Belimumab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 6 | 69 years STANDARD_DEVIATION 6 | 69 years STANDARD_DEVIATION 6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 10 Participants | 4 Participants |
| Region of Enrollment United States | 11 participants | 17 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 9 Participants | 13 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 6 |
| other Total, other adverse events | 4 / 10 | 4 / 6 |
| serious Total, serious adverse events | 4 / 10 | 0 / 6 |
Outcome results
Primary
Percent Change of Circulating Anti-GRP78 IgG Levels
Anti-GRP78 IgG is a clinically relevant surrogate biomarker of autoimmunity in pulmonary emphysema patients who have clinically relevant (and quantifiable) autoimmune responses
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)
Population: Measured as Optical Density (OD) at 405 nM of ELISA. OD values are proportional to autoantibody concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Belimumab | Percent Change of Circulating Anti-GRP78 IgG Levels | -17.0 % change | Standard Error 5.4 |
| Placebo | Percent Change of Circulating Anti-GRP78 IgG Levels | -2.6 % change | Standard Error 5.1 |
Secondary
Adverse Events
Adverse events will be evaluated according to criteria outlined in the National Cancer Institure (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
Time frame: Study start to completion (7 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Belimumab | Adverse Events | 10 Adverse events |
| Placebo | Adverse Events | 4 Adverse events |
Secondary
Percent Change of Circulating B-cells
Treatment effect on relative percentages of circulating B-cells (CD20+) by flow cytometry
Time frame: Prior to treatment, and at treatment end on day 210 or when subject participation is terminated
Population: analyzed as % of CD20+ cells among peripheral blood mononuclear cells
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Belimumab | Percent Change of Circulating B-cells | -12.2 Percent change | Standard Error 4.9 |
| Placebo | Percent Change of Circulating B-cells | -5.0 Percent change | Standard Error 6.5 |
Secondary
Percent Change of Pneumococcal Polysaccharide-binding Antibodies
Treatment effects on concentrations of pneumococcal polysaccharide-binding antibodies by ELISA
Time frame: Prior to treatment and at end of treatment on day 210 (or the conclusion of treatment if subject withdraws)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Belimumab | Percent Change of Pneumococcal Polysaccharide-binding Antibodies | -14.1 Percent change | Standard Error 9.1 |
| Placebo | Percent Change of Pneumococcal Polysaccharide-binding Antibodies | -5.0 Percent change | Standard Error 6.5 |