Broccoli Sprout Extracts Trial to See if NRF2 is Enhanced by Sulforaphane Treatment in Patients With COPD

Study Overview
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Brief Summary
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Evidence from investigators' group has shown that chronic obstructive pulmonary disease (COPD) patients have impairment of antioxidant defenses which are caused by a defect in activity of Nrf2. This trial focuses on sulforaphane, a derivative of cruciferous vegetables, which is a potent stimulator of Nrf2 activity. The investigators want to investigate whether ingestion of sulforaphane by COPD patients will increase Nrf2 activity and expression of downstream antioxidants. Accordingly, the investigators are conducting a placebo-controlled randomized proof of principle trial of two oral doses of sulforaphane, 25 and 150 micromoles, for 4 weeks in 90 COPD patients. The investigators' goal is to establish a safe and tolerable dose of sulforaphane that effects in vivo antioxidants via Nrf2, then the investigators will have a novel candidate treatment for longer-term efficacy trials.

Detailed Description
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Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality in the United States and is a growing cause of chronic disease internationally. Presently, there are limited treatment options for this disease to modify the progression of airflow obstruction and decrease periodic exacerbations. Recent evidence has emphasized the central role of oxidative stress as a mechanism of COPD pathobiology. Evidence from investigators' group has shown that COPD patients and animals exposed to cigarette smoke have impairment of antioxidant defenses which are caused by a defect in activity of nuclear factor erythroid 2 like 2 (Nrf2), a prolific regulator of anti-oxidant enzymes, glutathione homeostasis, and cytoprotective proteins. Activation of Nrf2 protects mice with chronic smoke exposure from developing emphysema, decreases oxidative stress, increases proteasomal anti-apoptotic cytoprotective responses, improves bacterial phagocytosis and killing, and reverses tobacco-smoke induced corticosteroid resistance. Similarly, in vitro Nrf2 activation in human COPD lung cells has shown improved cytoprotection, improved bacterial clearance, and restoration of steroid sensitivity. This trial focuses on sulforaphane, a derivative of cruciferous vegetables, which is a potent in vitro and in vivo stimulator of Nrf2 activity. The investigators want to investigate whether ingestion of sulforaphane by chronic obstructive pulmonary disease (COPD) patients will increase Nrf2 activity and expression of downstream antioxidants in alveolar macrophages and bronchial epithelial cells. Accordingly, the investigators are conducting a placebo-controlled randomized proof of principle trial of two oral doses of sulforaphane, 25 and 150 micromoles, for 4 weeks in 90 COPD patients. Collections of alveolar macrophages by Bronchoalveolar lavage (BAL), bronchial epithelial cells by endobronchial brushings will be performed at baseline and 4 weeks. Other bio-specimens will include nasal epithelial cells, Peripheral Blood Monocyte Collection (PBMCs), and expired breath condensate (EBC). The investigators' goal is to establish a safe and tolerable dose of sulforaphane that effects in vivo antioxidants via Nrf2, then the investigators will have a novel candidate treatment for longer-term efficacy trials. Ancillary studies are proposed to explore the efficacy and mechanisms of sulforaphane to increase bacterial clearance and to restore steroid sensitivity in COPD lung cells.

Official Title
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Enhancing Nrf2 by Sulforaphane Treatment in COPD

Conditions
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COPD

Intervention / Treatment
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* Drug: Sulforaphane 25
* Dietary Supplement: Sulforaphane 150
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 40 years or greater, either sex 10 or more pack-years smoking history Physician diagnosed COPD Post bronchodilator Forced expiratory volume in 1 second (FEV1)/ forced expiratory vital capacity (FVC) ratio < 0.70 FEV1 40-80 % predicted Willingness to ingest no more than 1 serving of cruciferous vegetables per week during run-in and treatment periods Ability and willingness to provide informed consent Exclusion Criteria: COPD exacerbation within preceding 6 weeks requiring treatment Significant respiratory (other than COPD), cardiovascular, neuropsychiatric, renal, gastrointestinal, or genitourinary disease that would interfere with participation in the study or interpretation of the results. Acute Myocardial infarction (MI) or Acute Coronary syndrome within 6 prior months Cancer (other than skin or localized prostate) within preceding 5 years Child-bearing potential with lack of adequate contraception, Pregnancy or lactation. Acceptable forms of birth control include abstinence, hysterectomy, tubal ligation, two of the following: vasectomy, condom, diaphragm, intrauterine device, oral or implanted contraceptives, or spermicide. Allergy to local anesthesia Resting hypoxemia (O2 saturation < 90%) Glomerular Filtration Rate (GFR) < 30 Liver enzymes four times upper normal Current use of warfarin for any indication

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sulforaphane 25<br>25 micromoles (4.4 mg) sulforaphane daily by mouth | Drug: Sulforaphane 25<br>* 25 micromoles (4.4 mg) sulforaphane daily by mouth<br>* Other names: This is derived from broccoli sprouts.;|
| Active Comparator: Sulforaphane 150<br>150 micromoles (26.6 mg) sulforaphane daily by mouth | Dietary Supplement: Sulforaphane 150<br>* 150 micromoles (26.6 mg) sulforaphane daily by mouth<br>|
| Placebo Comparator: Placebo<br>Microcrystalline cellulose | Other: Placebo<br>* Microcrystalline cellulose once daily by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | The first primary design variable is the change from baseline in nuclear factor erythroid 2 like 2 (Nrf2) expression in alveolar macrophages (AM) at 4 weeks by analysing Nrf2 protein and expression of a panel of Nrf2 regulated genes.Three participants - one from each treatment group - were unable to complete follow-up bronchoalveolar lavage for primary outcome data. | Baseline and 4 weeks | 
| Change From Baseline in Bronchial Epithelial Cell Expression of Nrf2 at 4 Weeks | The second primary design variable is the change from baseline in nuclear factor erythroid 2 like 2 (Nrf2) expression in bronchial epithelial cells (BEC) at 4 weeks by analysing Nrf2 protein. Three participants - one from each treatment group - were unable to complete follow-up bronchoalveolar lavage for primary outcome data. | Baseline and 4 weeks | 
| Change From Baseline in Bronchial Epithelial Cell Expression of NQ01 and Keap1 at 4 Weeks | The third primary design variable is the change from baseline in NAD(P)H Quinone Dehydrogenase 1 (NQ01) and Kelch Like ECH Associated Protein 1 (Keap1) expression in bronchial epithelial cells (BEC) at 4 weeks. Three participants - one from each treatment group - were unable to complete follow-up bronchoalveolar lavage for primary outcome data. | Baseline and 4 weeks | 
| Change From Baseline in Bronchial Epithelial Cell Expression of HO1 at 4 Weeks | The fourth primary design variable is the change from baseline in expression of Heme Oxygenase 1 (HO1) in bronchial epithelial cells (BEC) at 4 weeks. Three participants - one from each treatment group - were unable to complete follow-up bronchoalveolar lavage for primary outcome data. | Baseline and 4 weeks | 
| Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C1 at 4 Weeks | The fifth primary design variable is the change from baseline in expression of Aldo-Keto Reductase Family 1 Member C1 (AKR1C1) in bronchial epithelial cells (BEC) at 4 weeks. Three participants - one from each treatment group - were unable to complete follow-up bronchoalveolar lavage for primary outcome data. | Baseline and 4 weeks | 
| Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C3 at 4 Weeks | The sixth primary design variable is the change from baseline in expression of Aldo-Keto Reductase Family 1 Member C3 (AKR1C3) in bronchial epithelial cells (BEC) at 4 weeks. Three participants - one from each treatment group - were unable to complete follow-up bronchoalveolar lavage for primary outcome data. | Baseline and 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fold-change in Isoprostane Concentrations (Follow-up to Baseline) | Isoprostane, an oxidant stress indicator, was measured in expired breath condensate at baseline and 4 weeks. | Baseline and 4 weeks | 
| Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | Inflammatory markers were measured in serum samples derived from venipuncture at baseline and 4 weeks in the serum of the participants of the trial. | Baseline and 4 weeks | 
| Fold-change in Inflammatory Marker Concentrations in Bronchial Alveolar Lavage (Follow-up to Baseline) by Treatment Group | Inflammatory markers were measured in bronchial alveolar lavage samples at baseline and 4 weeks in the participants of this trial who had bronchoalveolar lavage samples obtained.Three participants - one from each treatment group - were unable to complete follow-up bronchoalveolar lavage. | Baseline and 4 weeks | 
| Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) | Inflammatory markers were measured in plasma at baseline and 4 weeks. Thiobarbituric acid reactive substances were measured in nmol malondialdehyde (MDA)/mL. | Baseline and 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Nrf2, Sulforaphane