Oral resveratrol supplementation in bronchiectasis

INTERVENTION: This is a pilot study evaluating the anti‐inflammatory and antioxidant effects of high dose oral resveratrol supplementation. Resveratrol is a naturally‐occurring antioxidant, that has antimicrobial and anti‐inflammatory properties. It is commercially available as a nutritional supplement, commonly at much lower doses than will be used in this study. We intend to conduct a single centre, open label, pre‐post, pilot study of 40 participants. The duration of treatment in this study is 12 weeks, with a preceding 4 week screening period (during which participants will need to remain stable/free of exacerbations). All participants will take a commercially available product, "Transmax", which is taken orally as a capsule. Each capsule contains 500mg of resveratrol (with the addition of 5mg piperine and 5mg of polydatin: polydatin is a precursor of resveratrol and piperine is an extract of black pepper. Both increase oral bioavailability of resveratrol). Within the study, we will evaluate the optimal dosage of resveratrol in bronchiectasis. i) Half of participants (20 out of 40) will be randomised to receive 500mg of resveratrol (one capsule) twice a day. ii) The other half will be randomised to receive 1000mg (two capsules) twice a day. All participants and investigators will be aware of the dosages taken; participants will take either 500mg twice a day or 1000mg twice a day. This will help to determine the optimal dose of resveratrol supplementation in bronchiectasis, to guide a future, larger clinical trial that will evaluate clinical end‐points. All participants will take resveratrol for 12 weeks, irrespective of the dosage provided. Patients will be required to attend Middlemore Hospital, Auckla CONDITION: Bronchiectasis; ; Bronchiectasis Respiratory ‐ Other respiratory disorders / diseases PRIMARY OUTCOME: Sputum neutrophil elastase[Baseline and 12 weeks] SECONDARY OUTCOME: Health‐related Quality of Life in bronchiectasis patients ; • St. George’s Respiratory Questionnaire (SGRQ) ; • Bronchiectasis Health Questionnaire (BHQ) ; • Leicester Cough Questionnaire (LCQ)[Baseline and 12 weeks] Lung function (FEV1, FVC) , measured using spirometry[Baseline and 12 weeks] Markers of airway infection: ; ‐ sputum culture ; [Baseline and 12 weeks] Markers of airway infection: ; ‐ sputum levels of cathelicidin antimicrobial peptide (LL‐37) [Baseline and 12 weeks] Markers of airway infection: ; ‐ sputum procalcitonin ; [Baseline and 12 weeks] Markers of airway inflammation: ; ‐ sputum C‐reactive protein ; [Baseline and 12 weeks] Markers of airway inflammation: ; ‐ sputum cytokines (GM‐CSF, IL‐1B, IL‐6, IL‐8, TNF‐alpha)[Baseline and 12 weeks] Markers of airway inflammation: ; ‐ sputum purulence ( as determined by the sputum purulence chart, which is a validated measure of neutrophilic inflammation in the airways of patients with bronchiectasis) ; [Baseline and 12 weeks] Measurement of antioxidant status in sputum and serum: Total Antioxidant Capacity (TAC) ; ‐ TAC is a is a widely‐used measure of overall antioxidant status, and has previously been used in studies involving resveratrol ; ‐ TAC levels in sputum have not previously been performed[Baseline and 12 weeks] Measurement of resveratrol levels (and metabolites) in serum and sputum ; ‐ resveratrol has been shown to accumulate in tissues (e.g. liver, muscle) with local effects; measurement of levels in sputum has not previously been performed ; ; ; ; ; ‐ However, resveratrol supplementation has not been studied in respiratory conditions such as bronchiectasis ; ; ‐ Therefore safety will be measured by regularly assessing for adverse events (as per the severity grading system Common Terminology Criteria for Adverse Events (CTCAE v. 3.0) or side effects. ; ‐ Participants will be instructed to take the morning resveratrol dose 30 minutes prior to the visit; time of dosing will be recorded. Levels will be taken at 90 minutes post‐dose[Baseline and 12 weeks] Number of pulmonary exacerbations ; ‐ as defined in the European Respiratory Society consensus definition: "a person with bronchiectasis with a deterioration in three or more of the following key symptoms for at least 48 h: cough; sputum volume and/or consistency; sputum purulence; breathlessness and/or exercise tolerance; fatigue and/or malaise; haemoptysis AND a clinician determines that a change in bronchiectasis treatment is required" ; ‐ This will be assessed during study visits and phone calls. The diary card also contains all of these components which will allow us to determine the suitability of antibiotic prescription in the community[Baseline and 12 weeks. ; This will also be reviewed and discussed with patients at the scheduled study visits, and with scheduled telephone contact at weeks 2 and 8 of the study.] Safety of oral resveratrol supplementation in bronchiectasis ; ‐ The safety of resveratrol has been demonstrated in a range of non‐respiratory conditions. Doses up to 5 g daily in healthy volunteers were safe and well‐tolerated, with mild adverse effects (gastrointestinal disturbance, headache and myalgia). ; ; ‐ Participants will also be requested to documents any symptoms or concerns in their diary cards provided throughout the study, and encouraged to contact a member of the study team if they develop any new symptoms. ; ; ; [Baseline and 12 weeks (see above for further details). ; ; ‐ This will be performed at study visits (weeks 0, 4, and 12) and through the scheduled telephone calls on weeks 2 and 8. Participants (or other healthcare worker e.g. GP) can contact the study team at any point during the study if there are questions or concerns regarding this aspect of the study.] Time to first pulmonary exacerbation ; ‐ as defined in the European Respiratory Society consensus definition: "a person with bronchiectasis with a deterioration in three or more of the following key symptoms for at least 48 h: cough; sputum volume and/or consistency; sputum purulence; breathlessness and/or exercise tolerance; fatigue and/or malaise; haemoptysis AND a clinician determines that a change in bronchiectasis treatment is required" ; ; ‐ This will be assessed during study visits and phone calls. The diary card also contains all of these components which will allow us to determine the suitability of antibiotic prescription in the community ; [Baseline and 12 weeks. ; ; This will also be reviewed and discussed with patients at the scheduled study visits, and with scheduled telephone contact at weeks 2 and 8 of the study. ; ] Tolerability of resveratrol and adherence ; ‐ these will be assessed by counting returned capsules after asking patients to bring issued medication to each study visit. They will also document daily administration in their daily diary cards ; ‐ tolerability will be defined as successful completion of the study ; ‐ adherence will be described as percentage of capsules taken calculated from prescribed and returned medication ; ‐ we will record participation consent probability, recruitment and drop‐out events[Diary cards will be reviewed during each study visits (weeks 4 and 12), and capsules will be counted at study visits at week 4 and 12] INCLUSION CRITERIA: • Aged 18 years or over • Able to provide written informed consent • Able to provide spontaneous sputum sample at visit 2 (week 0) • High‐resolution CT (HRCT) chest scan confirming bronchiectasis within the last 5 years • Clinically stable during baseline period, for 4 weeks before treatment commencement (defined as absence of clinical worsening beyond normal daily variation, with no need for increasing habitual medications or taking antibiotics or prednisone and stable spirometry) • History of at least 1 pulmonary exacerbation requiring antibiotics in the past 12 months Patients with asthma and/or COPD will be included if the primary diagnosis is bronchiectasis