COPD
Conditions
Keywords
COPD, Nrf2, Sulforaphane
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.
Interventions
DRUGSulforaphane 25
25 micromoles (4.4 mg) sulforaphane daily by mouth
DIETARY_SUPPLEMENTSulforaphane 150
150 micromoles (26.6 mg) sulforaphane daily by mouth
OTHERPlacebo
Microcrystalline cellulose once daily by mouth
Sponsors
Temple University
State University of New York at Buffalo
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C3 at 4 Weeks | 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. |
| Change From Baseline in Bronchial Epithelial Cell Expression of Nrf2 at 4 Weeks | 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 | 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 | 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 | 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 Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | 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 | 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) | 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. |
| Fold-change in Isoprostane Concentrations (Follow-up to Baseline) | Baseline and 4 weeks | Isoprostane, an oxidant stress indicator, was measured in expired breath condensate at baseline and 4 weeks. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Microcrystalline cellulose
Placebo: Microcrystalline cellulose once daily by mouth | 31 |
| Sulforaphane 25 25 micromoles (4.4 mg) sulforaphane daily by mouth
Sulforaphane 25: 25 micromoles (4.4 mg) sulforaphane daily by mouth | 29 |
| Sulforaphane 150 150 micromoles (26.6 mg) sulforaphane daily by mouth
Sulforaphane 150: 150 micromoles (26.6 mg) sulforaphane daily by mouth | 29 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Did not complete bronchoscopy | 1 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Sulforaphane 25 | Sulforaphane 150 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 5 Participants | 10 Participants | 24 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 24 Participants | 19 Participants | 65 Participants |
| Age, Continuous | 59 years | 59 years | 56 years | 58 years |
| Chronic obstructive pulmonary disease (COPD) characteristics 10 or more pack years of smoking history | 30 participants | 29 participants | 29 participants | 88 participants |
| Chronic obstructive pulmonary disease (COPD) characteristics COPD exacerbation in last 12 months | 5 participants | 7 participants | 7 participants | 19 participants |
| Chronic obstructive pulmonary disease (COPD) characteristics Smoke 10 or more cigarettes a day now | 10 participants | 9 participants | 10 participants | 29 participants |
| Chronic obstructive pulmonary disease (COPD) characteristics Smoke cigarettes now | 20 participants | 16 participants | 18 participants | 54 participants |
| Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) | 14.8 mL/mmHg/min | 15.7 mL/mmHg/min | 16.3 mL/mmHg/min | 15.7 mL/mmHg/min |
| Medical Research Council Dyspnea Score | 2 units on a scale | 2 units on a scale | 2 units on a scale | 2 units on a scale |
| Post bronchodilator FEV1 | 61 percent predicted | 54 percent predicted | 65 percent predicted | 61 percent predicted |
| Post bronchodilator FEV1/FVC ratio | 0.56 ratio | 0.52 ratio | 0.57 ratio | 0.56 ratio |
| Pulmonary function measures Forced residual capacity | 3.6 Liters | 3.6 Liters | 3.4 Liters | 3.5 Liters |
| Pulmonary function measures Residual volume | 2.6 Liters | 2.6 Liters | 2.7 Liters | 2.6 Liters |
| Pulmonary function measures Slow vital capacity | 3.1 Liters | 3.0 Liters | 3.7 Liters | 3.3 Liters |
| Pulmonary function measures Total lung capacity | 6.0 Liters | 5.5 Liters | 6.3 Liters | 6.0 Liters |
| Pulse oximetry (SpO2) | 95 Percentage of oxyhemoglobin | 96 Percentage of oxyhemoglobin | 96 Percentage of oxyhemoglobin | 96 Percentage of oxyhemoglobin |
| Region of Enrollment United States | 31 participants | 29 participants | 29 participants | 89 participants |
| Sex: Female, Male Female | 15 Participants | 12 Participants | 8 Participants | 35 Participants |
| Sex: Female, Male Male | 16 Participants | 17 Participants | 21 Participants | 54 Participants |
| St Georges Respiratory Questionnaire Activity score | 54 units on a scale | 60 units on a scale | 50 units on a scale | 55 units on a scale |
| St Georges Respiratory Questionnaire Impacts score | 27 units on a scale | 34 units on a scale | 26 units on a scale | 28 units on a scale |
| St Georges Respiratory Questionnaire Symptoms score | 58 units on a scale | 55 units on a scale | 50 units on a scale | 52 units on a scale |
| St Georges Respiratory Questionnaire Total score | 43 units on a scale | 47 units on a scale | 39 units on a scale | 40 units on a scale |
| Use of respiratory medications in prior 2 weeks Long-acting anticholinergic bronchodilator | 7 participants | 9 participants | 10 participants | 26 participants |
| Use of respiratory medications in prior 2 weeks Long-acting beta-agonist | 2 participants | 1 participants | 2 participants | 5 participants |
| Use of respiratory medications in prior 2 weeks Long-acting beta-agonist & inhaled corticosteroid | 14 participants | 13 participants | 13 participants | 40 participants |
| Use of respiratory medications in prior 2 weeks Short-acting beta-agonist | 22 participants | 21 participants | 18 participants | 61 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 31 | 21 / 29 | 18 / 29 |
| serious Total, serious adverse events | 0 / 31 | 2 / 29 | 1 / 29 |
Outcome results
Primary
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.
Time frame: Baseline and 4 weeks
Population: Number of participants analyzed based on number of individuals with alveolar macrophage samples in which assays could be successfully performed. Assays failed for two participants in the placebo group, one in the 25 micromole group, and one in the 150 micromole group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | NQ01 | 0.80 fold change |
| Placebo | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | HO1 | 0.90 fold change |
| Placebo | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | AKR1C1 | 0.81 fold change |
| Placebo | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | AKR1C3 | 1.03 fold change |
| Placebo | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | Nrf2 | 1.14 fold change |
| Placebo | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | Keap1 | 0.94 fold change |
| Sulforaphane 25 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | Keap1 | 0.99 fold change |
| Sulforaphane 25 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | NQ01 | 1.03 fold change |
| Sulforaphane 25 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | AKR1C3 | 1.02 fold change |
| Sulforaphane 25 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | Nrf2 | 1.05 fold change |
| Sulforaphane 25 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | HO1 | 0.98 fold change |
| Sulforaphane 25 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | AKR1C1 | 1.13 fold change |
| Sulforaphane 150 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | HO1 | 1.06 fold change |
| Sulforaphane 150 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | AKR1C1 | 0.71 fold change |
| Sulforaphane 150 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | Keap1 | 1.06 fold change |
| Sulforaphane 150 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | AKR1C3 | 0.87 fold change |
| Sulforaphane 150 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | NQ01 | 0.94 fold change |
| Sulforaphane 150 | Change From Baseline in Alveolar Macrophage Expression of Nrf2 and Associated Genes at 4 Weeks | Nrf2 | 1.13 fold change |
Comparison: Applies to gene expression of NAD(P)H Quinone Dehydrogenase 1 (NQ01) in alveolar macrophagesp-value: 0.45Kruskal-Wallis
Comparison: Applies to gene expression of Heme Oxygenase 1 (HO1) in alveolar macrophagesp-value: 0.4Kruskal-Wallis
Comparison: Applies to gene expression of Aldo-Keto Reductase Family 1 Member C1 (AKR1C1) in alveolar macrophagesp-value: 0.75Kruskal-Wallis
Comparison: Applies to gene expression of Aldo-Keto Reductase Family 1 Member C3 (AKR1C3) in alveolar macrophagesp-value: 0.49Kruskal-Wallis
Comparison: Applies to gene expression of nuclear factor erythroid 2 like 2 (Nrf2) in alveolar macrophagesp-value: 0.88Kruskal-Wallis
Comparison: Applies to gene expression of Kelch Like ECH Associated Protein 1 (Keap1) in alveolar macrophagesp-value: 0.71Kruskal-Wallis
Primary
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.
Time frame: Baseline and 4 weeks
Population: Number of participants analyzed based on number of individuals with alveolar macrophage samples in which assays could be successfully performed. Assays failed for two participants in the placebo group and two in the 150 micromole group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C1 at 4 Weeks | 1.45 fold change |
| Sulforaphane 25 | Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C1 at 4 Weeks | 1.08 fold change |
| Sulforaphane 150 | Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C1 at 4 Weeks | 0.79 fold change |
Comparison: Applies to gene expression of Aldo-Keto Reductase Family 1 Member C1 (AKR1C1) in bronchial epithelial cells.p-value: <0.01Kruskal-Wallis
Primary
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.
Time frame: Baseline and 4 weeks
Population: Number of participants analyzed based on number of individuals with bronchial epithelial samples in which assays could be successfully performed. Assays failed for two participants in the placebo group, one participant in the 25 micromole group, and one participant in the 150 micromole group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C3 at 4 Weeks | 1.10 fold change |
| Sulforaphane 25 | Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C3 at 4 Weeks | 1.38 fold change |
| Sulforaphane 150 | Change From Baseline in Bronchial Epithelial Cell Expression of AKR1C3 at 4 Weeks | 0.87 fold change |
Comparison: Applies to gene expression of Aldo-Keto Reductase Family 1 Member C3 (AKR1C3) in bronchial epithelial cells.p-value: 0.06Kruskal-Wallis
Primary
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.
Time frame: Baseline and 4 weeks
Population: Number of participants analyzed based on number of individuals with bronchial epithelial samples in which assays could be successfully performed. Assays failed for one participant in the placebo group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline in Bronchial Epithelial Cell Expression of HO1 at 4 Weeks | 1.05 fold change |
| Sulforaphane 25 | Change From Baseline in Bronchial Epithelial Cell Expression of HO1 at 4 Weeks | 1.12 fold change |
| Sulforaphane 150 | Change From Baseline in Bronchial Epithelial Cell Expression of HO1 at 4 Weeks | 0.93 fold change |
Comparison: Applies to gene expression of Heme Oxygenase 1 (HO1) in bronchial epithelial cellsp-value: 0.53Kruskal-Wallis
Primary
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.
Time frame: Baseline and 4 weeks
Population: Number of participants analyzed based on number of individuals with bronchial epithelial samples in which assays could be successfully performed. Assays failed for two participants in the placebo group and one in the 150 micromole group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Change From Baseline in Bronchial Epithelial Cell Expression of NQ01 and Keap1 at 4 Weeks | NQ01 | 1.09 fold change |
| Placebo | Change From Baseline in Bronchial Epithelial Cell Expression of NQ01 and Keap1 at 4 Weeks | KEAP1 | 1.12 fold change |
| Sulforaphane 25 | Change From Baseline in Bronchial Epithelial Cell Expression of NQ01 and Keap1 at 4 Weeks | NQ01 | 1.12 fold change |
| Sulforaphane 25 | Change From Baseline in Bronchial Epithelial Cell Expression of NQ01 and Keap1 at 4 Weeks | KEAP1 | 1.39 fold change |
| Sulforaphane 150 | Change From Baseline in Bronchial Epithelial Cell Expression of NQ01 and Keap1 at 4 Weeks | NQ01 | 0.96 fold change |
| Sulforaphane 150 | Change From Baseline in Bronchial Epithelial Cell Expression of NQ01 and Keap1 at 4 Weeks | KEAP1 | 0.87 fold change |
Comparison: Applies to gene expression of NAD(P)H Quinone Dehydrogenase 1 (NQ01) in bronchial epithelial cellsp-value: 0.69Kruskal-Wallis
Comparison: Applies to gene expression of Kelch Like ECH Associated Protein 1 (Keap1) in bronchial epithelial cellsp-value: <0.01Kruskal-Wallis
Primary
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.
Time frame: Baseline and 4 weeks
Population: Number of participants analyzed based on number of individuals with bronchial epithelial samples in which assays could be successfully performed. Assays failed for one participant in the placebo group and one in the 25 micromole group..
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline in Bronchial Epithelial Cell Expression of Nrf2 at 4 Weeks | 1.09 fold change |
| Sulforaphane 25 | Change From Baseline in Bronchial Epithelial Cell Expression of Nrf2 at 4 Weeks | 1.06 fold change |
| Sulforaphane 150 | Change From Baseline in Bronchial Epithelial Cell Expression of Nrf2 at 4 Weeks | 1.06 fold change |
Comparison: Applies to gene expression of Nrf2 in bronchial epithelial cellsp-value: 0.68Kruskal-Wallis
Secondary
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.
Time frame: Baseline and 4 weeks
Population: Number of participants analyzed is based on number of participants that had bronchial alveolar lavage samples available. Samples were missing for two participants in the placebo group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Fold-change in Inflammatory Marker Concentrations in Bronchial Alveolar Lavage (Follow-up to Baseline) by Treatment Group | Interleukin-8 (pg/mg) | 1.22 fold change |
| Placebo | Fold-change in Inflammatory Marker Concentrations in Bronchial Alveolar Lavage (Follow-up to Baseline) by Treatment Group | Secretory leukoprotease inhibitor (pg/mg) | 1.51 fold change |
| Sulforaphane 25 | Fold-change in Inflammatory Marker Concentrations in Bronchial Alveolar Lavage (Follow-up to Baseline) by Treatment Group | Interleukin-8 (pg/mg) | 0.94 fold change |
| Sulforaphane 25 | Fold-change in Inflammatory Marker Concentrations in Bronchial Alveolar Lavage (Follow-up to Baseline) by Treatment Group | Secretory leukoprotease inhibitor (pg/mg) | 1.09 fold change |
| Sulforaphane 150 | Fold-change in Inflammatory Marker Concentrations in Bronchial Alveolar Lavage (Follow-up to Baseline) by Treatment Group | Interleukin-8 (pg/mg) | 1.11 fold change |
| Sulforaphane 150 | Fold-change in Inflammatory Marker Concentrations in Bronchial Alveolar Lavage (Follow-up to Baseline) by Treatment Group | Secretory leukoprotease inhibitor (pg/mg) | 1.12 fold change |
Comparison: Applies to interleukin-8 resultsp-value: 0.71Kruskal-Wallis
Comparison: Applies to secretory leukoprotease inhibitor resultsp-value: 0.33Kruskal-Wallis
Secondary
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.
Time frame: Baseline and 4 weeks
Population: Number of participants analyzed based on number of individuals with expired breath condensate samples in which testing could be successfully performed. Samples were missing for two participants in the 25 micromole group and one participant in the 150 micromole group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Fold-change in Isoprostane Concentrations (Follow-up to Baseline) | 1.18 fold change |
| Sulforaphane 25 | Fold-change in Isoprostane Concentrations (Follow-up to Baseline) | 0.83 fold change |
| Sulforaphane 150 | Fold-change in Isoprostane Concentrations (Follow-up to Baseline) | 0.64 fold change |
p-value: 0.2Kruskal-Wallis
Secondary
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.
Time frame: Baseline and 4 weeks
Population: Number of participants analyzed is based on number of participants that had plasma samples available. Samples were missing for one participant in the 25 micromole group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) | Thiobarbituric acid reactive substances | 0.96 fold change |
| Placebo | Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) | Isoprostane (ng/mg) | 0.89 fold change |
| Placebo | Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) | Total antioxidants (mM Trolox equivalents/L) | 0.97 fold change |
| Sulforaphane 25 | Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) | Thiobarbituric acid reactive substances | 1.05 fold change |
| Sulforaphane 25 | Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) | Isoprostane (ng/mg) | 0.90 fold change |
| Sulforaphane 25 | Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) | Total antioxidants (mM Trolox equivalents/L) | 0.92 fold change |
| Sulforaphane 150 | Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) | Isoprostane (ng/mg) | 0.88 fold change |
| Sulforaphane 150 | Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) | Total antioxidants (mM Trolox equivalents/L) | 0.97 fold change |
| Sulforaphane 150 | Fold-change in Plasma Inflammatory Marker Concentrations (Follow-up to Baseline) | Thiobarbituric acid reactive substances | 1.06 fold change |
Comparison: Applies to isoprostane results.p-value: 0.8Kruskal-Wallis
Comparison: Applies to thiobarbituric acid reactive substances results.p-value: 0.35Kruskal-Wallis
Comparison: Applies to total antioxidants results.p-value: 0.53Kruskal-Wallis
Secondary
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.
Time frame: Baseline and 4 weeks
Population: Number of participants analyzed is based on number of participants that had plasma samples available. Samples were missing for one participant in the 25 micromole group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | Interleukin-8 (pg/mL) | 1.06 fold change |
| Placebo | Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | Interleukin-6 (pg/mL) | 0.75 fold change |
| Placebo | Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | C-reactive protein (mg/L) | 0.99 fold change |
| Sulforaphane 25 | Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | Interleukin-8 (pg/mL) | 1.04 fold change |
| Sulforaphane 25 | Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | C-reactive protein (mg/L) | 0.90 fold change |
| Sulforaphane 25 | Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | Interleukin-6 (pg/mL) | 0.90 fold change |
| Sulforaphane 150 | Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | Interleukin-8 (pg/mL) | 1.03 fold change |
| Sulforaphane 150 | Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | Interleukin-6 (pg/mL) | 1.12 fold change |
| Sulforaphane 150 | Fold-change in Serum Inflammatory Marker Concentrations (Follow-up to Baseline) | C-reactive protein (mg/L) | 1.01 fold change |
Comparison: Applies to C-reactive protein concentrationp-value: 0.41Kruskal-Wallis
Comparison: Applies to Interleukin-6 concentrationp-value: 0.07Kruskal-Wallis
Comparison: Applies to Interleukin-8 concentrationp-value: 0.65Kruskal-Wallis