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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01335971
First Posted: April 15, 2011
Last Update Posted: May 19, 2017
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. Read our disclaimer for details.
Collaborators:
Temple University
State University of New York at Buffalo
Information provided by (Responsible Party):
Johns Hopkins University
April 8, 2011
April 15, 2011
August 25, 2016
May 19, 2017
May 19, 2017
September 2010
July 2013   (Final data collection date for primary outcome measure)
  • Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks [ Time Frame: Baseline and 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.
  • Change From Baseline in Bronchial Epithelial Cell Expression of Nrf2 at 4 Weeks [ Time Frame: Baseline and 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.
  • Change From Baseline in Bronchial Epithelial Cell Expression of NQ01 and Keap1 at 4 Weeks [ Time Frame: Baseline and 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.
  • Change From Baseline in Bronchial Epithelial Cell Expression of HO1 at 4 Weeks [ Time Frame: Baseline and 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.
  • Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C1 at 4 Weeks [ Time Frame: Baseline and 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.
  • Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C3 at 4 Weeks [ Time Frame: Baseline and 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.
  • Nrf2 levels and downstream anti-oxidants [ Time Frame: 4 weeks ]
    The primary design variable is the change in Nrf2 expression in alveolar macrophages (AM)/bronchial epithelial cells (BEC).
  • Support of Antioxidant Effects [ Time Frame: 4 weeks ]
    Support of antioxidant effects will be quantified by changes in phase II anti-oxidant gene expression (NQ01, HO-1, GPX2, GCLM, GCLC, GSTA1).
Complete list of historical versions of study NCT01335971 on ClinicalTrials.gov Archive Site
  • Fold-change in Isoprostane Concentrations (Follow-up to Baseline) [ Time Frame: Baseline and 4 weeks ]
    Isoprostane, an oxidant stress indicator, was measured in expired breath condensate at baseline and 4 weeks.
  • Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) [ Time Frame: Baseline and 4 weeks ]
    Inflammatory markers were measured in serum samples derived from venipuncture at baseline and 4 weeks in the serum of the participants of the trial.
  • Fold-change in Inflammatory Marker Concentrations in Bronchial Alveolar Lavage (Follow-up to Baseline) by Treatment Group [ Time Frame: Baseline and 4 weeks ]
    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.
  • Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) [ Time Frame: Baseline and 4 weeks ]
    Inflammatory markers were measured in plasma at baseline and 4 weeks. Thiobarbituric acid reactive substances were measured in nmol malondialdehyde (MDA)/mL.
  • Oxidative Stress will be Measured in Plasma and Expired Breath [ Time Frame: 4 weeks ]
    Oxidant stress indicators (isoprostane) will be measured in plasma and expired breath.
  • Measures of Airway Inflammation [ Time Frame: 4 weeks ]
    Measured as BAL cell counts and cytokine profiles
  • Are There Short-Term Functional Effects of Treatment? [ Time Frame: 4 weeks ]
    Pulmonary function tests - Spirometry, lung volumes, DLCO will be measured to determine whether there are any short-term functional effects of the treatment.
  • Patient Reported Outcomes [ Time Frame: 4 weeks ]
    MRC dyspnea scale and SGRQ which included questions on cough and sputum production.
  • Adverse Event Reporting [ Time Frame: 4 weeks ]
    Both spontaneous reports as well as targeted symptoms related to respiratory and GI systems will be included. Adverse events will be scored based on the NCI Common Toxicity Criteria rating scale.
  • Safety Measures to be Included in the Study [ Time Frame: 4 weeks ]
    Include baseline (V1) and follow-up (V4) CBC and biochemical profile including renal function, thyroid function, and liver function tests. Women of childbearing potential will have a pregnancy test at V1 and V4.
Not Provided
Not Provided
 
Broccoli Sprout Extracts Trial to See if NRF2 is Enhanced by Sulforaphane Treatment in Patients With COPD
Enhancing Nrf2 by Sulforaphane Treatment in COPD
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.
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.
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
COPD
  • Drug: Sulforaphane 25
    25 micromoles (4.4 mg) sulforaphane daily by mouth
    Other Name: This is derived from broccoli sprouts.
  • Dietary Supplement: Sulforaphane 150
    150 micromoles (26.6 mg) sulforaphane daily by mouth
  • Other: Placebo
    Microcrystalline cellulose once daily by mouth
  • Active Comparator: Sulforaphane 25
    25 micromoles (4.4 mg) sulforaphane daily by mouth
    Intervention: Drug: Sulforaphane 25
  • Active Comparator: Sulforaphane 150
    150 micromoles (26.6 mg) sulforaphane daily by mouth
    Intervention: Dietary Supplement: Sulforaphane 150
  • Placebo Comparator: Placebo
    Microcrystalline cellulose
    Intervention: Other: Placebo
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. Erratum in: PLoS One. 2017 Mar 28;12 (3):e0175077.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
89
June 2015
July 2013   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
40 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01335971
1U01HL105569( U.S. NIH Grant/Contract )
RFA-HL-10-003 ( Other Identifier: NHLBI )
Yes
Not Provided
Plan to Share IPD: Yes
Plan Description: The primary method of data-sharing will be through the traditional mechanism of publication of results in the peer-reviewed medical literature. Following publication of the main results, in accordance with NIH policy, a de-identified, HIPAA-compliant limited use dataset will be made available to qualified investigators who have Institutional Review Board approval and sign a data-use agreement. De-identified specimens collected in the study that are not analyzed for the main study will be made available to qualified investigators along with a limited use dataset in line with University and Office of Human Research Protections guidelines with a materials transfer agreement and/or data-use agreement as applicable. The Center for Clinical Trials has extensive experience in preparation of limited use datasets, and maintains policies and model agreements for data-use agreements and materials-transfer agreements.
Johns Hopkins University
Johns Hopkins University
  • Temple University
  • State University of New York at Buffalo
Principal Investigator: Janet T Holbrook, PhD, MPH Johns Hopkins Bloomberg School of Public Health
Johns Hopkins University
April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP
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