Clinical trial NCT01335971: Broccoli Sprout Extracts Trial to See if NRF2 is Enhanced by Sulforaphane Treatment in Patients With COPD
Official title: Enhancing Nrf2 by Sulforaphane Treatment in COPD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COPD
Keywords: COPD
Nrf2
Sulforaphane
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Temple University
name: State University of New York at Buffalo
First posted: 2011-04-15
Enrollment: 89
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks
timeFrame: Baseline and 4 weeks
measure: Change From Baseline in Bronchial Epithelial Cell Expression of Nrf2 at 4 Weeks
timeFrame: Baseline and 4 weeks
measure: Change From Baseline in Bronchial Epithelial Cell Expression of NQ01 and Keap1 at 4 Weeks
timeFrame: Baseline and 4 weeks
measure: Change From Baseline in Bronchial Epithelial Cell Expression of HO1 at 4 Weeks
timeFrame: Baseline and 4 weeks
measure: Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C1 at 4 Weeks
timeFrame: Baseline and 4 weeks
measure: Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C3 at 4 Weeks
timeFrame: Baseline and 4 weeks
Secondary outcomes:
measure: Fold-change in Isoprostane Concentrations (Follow-up to Baseline)
timeFrame: Baseline and 4 weeks
measure: Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline)
timeFrame: Baseline and 4 weeks
measure: Fold-change in Inflammatory Marker Concentrations in Bronchial Alveolar Lavage (Follow-up to Baseline) by Treatment Group
timeFrame: Baseline and 4 weeks
measure: Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline)
timeFrame: Baseline and 4 weeks
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins School of Medicine
state: Maryland
city: Buffalo
country: United States
facility: University at Baffalo, The State University of New York
state: New York
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
Study officials:
affiliation: Johns Hopkins Bloomberg School of Public Health
name: Janet T Holbrook, PhD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sidhaye VK, Holbrook JT, Burke A, Sudini KR, Sethi S, Criner GJ, Fahey JW, Berenson CS, Jacobs MR, Thimmulappa R, Wise RA, Biswal S. Compartmentalization of anti-oxidant and anti-inflammatory gene expression in current and former smokers with COPD. Respir Res. 2019 Aug 20;20(1):190. doi: 10.1186/s12931-019-1164-1.
citation: Wise RA, Holbrook JT, Criner G, Sethi S, Rayapudi S, Sudini KR, Sugar EA, Burke A, Thimmulappa R, Singh A, Talalay P, Fahey JW, Berenson CS, Jacobs MR, Biswal S; Broccoli Sprout Extract Trial Research Group. Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial. PLoS One. 2016 Nov 10;11(11):e0163716. doi: 10.1371/journal.pone.0163716. eCollection 2016.