ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 5 of 101 for:    Emphysema | Recruiting, Not yet recruiting, Available Studies | "Lung Diseases"

Belimumab Treatment of Emphysema Patients With Anti-GRP78 Autoantibodies (BOTEGA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03244059
Recruitment Status : Not yet recruiting
First Posted : August 9, 2017
Last Update Posted : August 9, 2018
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Mark Dransfield, MD, University of Alabama at Birmingham

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.

Condition or disease Intervention/treatment Phase
Chronic Obstructive Pulmonary Disease Emphysema Biological: Belimumab Drug: Placebo Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
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
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : August 2018
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Emphysema
Drug Information available for: Belimumab

Arm Intervention/treatment
Experimental: 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.
Biological: Belimumab
Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.
Other Name: Benlysta

Placebo Comparator: 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).
Drug: Placebo
An identically appearing placebo infusion.




Primary Outcome Measures :
  1. Reduction of circulating anti-GRP78 IgG levels [ Time Frame: Plasma concentrations of the anti-GRP78 autoantibodies will be measured pre-treatment, and at 1, 3, 5, and 7 months after treatment start. ]
    Anti-GRP78 IgG is a clinically relevant surrogate biomarker of autoimmunity in pulmonary emphysema patients who have clinically relevant (and quantifiable) autoimmune responses


Secondary Outcome Measures :
  1. Pneumococcal polysaccharide-binding antibodies [ Time Frame: Prior to treatment, and at 1, 3, 5, and 7 months after treatment starts ]
    Treatment effects on concentrations of pneumococcal polysaccharide-binding antibodies by ELISA

  2. Circulating B-cells [ Time Frame: Prior to treatment, and at 1, 3, 5, and 7 months after treatment starts ]
    Treatment effects on absolute numbers and phenotypes of circulating B-cells by flow cytometry

  3. Adverse Events [ Time Frame: Study start to completion (about 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03244059


Contacts
Contact: Steven R Duncan, MD (205) 934-5017 srduncan@uabmc.edu

Locations
United States, Alabama
UAB Lung Health Center
Birmingham, Alabama, United States, 35205
Sponsors and Collaborators
University of Alabama at Birmingham
GlaxoSmithKline

Responsible Party: Mark Dransfield, MD, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT03244059     History of Changes
Other Study ID Numbers: IRB-300000119
First Posted: August 9, 2017    Key Record Dates
Last Update Posted: August 9, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Mark Dransfield, MD, University of Alabama at Birmingham:
COPD
belimumab
biologic agent
GRP78

Additional relevant MeSH terms:
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Emphysema
Pulmonary Emphysema
Respiratory Tract Diseases
Pathologic Processes
Belimumab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs