Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000721909
Ethics application status
Approved
Date submitted
11/05/2020
Date registered
3/07/2020
Date last updated
3/07/2020
Date data sharing statement initially provided
3/07/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Oral resveratrol supplementation in bronchiectasis
Scientific title
Antioxidant and anti-inflammatory effects of resveratrol in adults with bronchiectasis
Secondary ID [1] 300784 0
HRC 20/653
Universal Trial Number (UTN)
U1111-1249-6903
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchiectasis 316646 0
Condition category
Condition code
Respiratory 314890 314890 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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, Auckland for 4 separate visits
1) Visit 1: 'Screening' visit, to evaluate a participant's suitability for the study (week 'minus 4')
2) Visit 2: Participants attend visit 2 to begin treatment (wither 500mg twice a day, or 1000mg twice a day (week 0).
3) Visit 3: at week 4 of treatment to review participants' progress on treatment
4) Visit 4: at week 12, to complete the study.

At each visit, participants will have a physical examination, provide a blood and sputum sample, complete quality of life questionnaires and perform spirometry (simple lung function test). Each visit is expected to last approximately 1 to 2 hours.

Resveratrol has been shown to be safe at doses up to 5 grams (5000mg) per day. Mild gastro-intestinal side-effects have been reported at the highest doses. Participants will be advised to contact the research team if adverse effects develop, and may be advised to reduce the dose of resveratrol after consultation with the study team.

Adherence will be monitored and measured by reviewing the number of capsules issued to patients as compared to the number of capsules returned at each subsequent visit. Patient's adherence with the proper use of the study drug or placebo will be assessed at visits 3 and 4, and patients will be reminded to bring all study product pack(s) (used or unused) and completed daily diary cards to these visits.
Intervention code [1] 317106 0
Treatment: Other
Comparator / control treatment
Participants in the study will receive 2 different doses of resveratrol to evaluate if 1000mg twice a day is superior to 500mg twice a day.
Control group
Dose comparison

Outcomes
Primary outcome [1] 323217 0
Sputum neutrophil elastase
Timepoint [1] 323217 0
Baseline and 12 weeks
Secondary outcome [1] 382700 0
Markers of airway inflammation:
- sputum cytokines (GM-CSF, IL-1B, IL-6, IL-8, TNF-alpha)
Timepoint [1] 382700 0
Baseline and 12 weeks
Secondary outcome [2] 382702 0
Markers of airway infection:
- sputum levels of cathelicidin antimicrobial peptide (LL-37)
Timepoint [2] 382702 0
Baseline and 12 weeks
Secondary outcome [3] 382703 0
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
Timepoint [3] 382703 0
Baseline and 12 weeks
Secondary outcome [4] 382705 0
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
- 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
Timepoint [4] 382705 0
Baseline and 12 weeks
Secondary outcome [5] 382712 0
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
Timepoint [5] 382712 0
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.
Secondary outcome [6] 382713 0
Lung function (FEV1, FVC) , measured using spirometry
Timepoint [6] 382713 0
Baseline and 12 weeks
Secondary outcome [7] 382714 0
Health-related Quality of Life in bronchiectasis patients
• St. George’s Respiratory Questionnaire (SGRQ)
• Bronchiectasis Health Questionnaire (BHQ)
• Leicester Cough Questionnaire (LCQ)
Timepoint [7] 382714 0
Baseline and 12 weeks
Secondary outcome [8] 382715 0
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).

- 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 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.
Timepoint [8] 382715 0
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.
Secondary outcome [9] 382717 0
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
Timepoint [9] 382717 0
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
Secondary outcome [10] 383263 0
Markers of airway inflammation:
- sputum C-reactive protein
Timepoint [10] 383263 0
Baseline and 12 weeks
Secondary outcome [11] 383264 0
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)
Timepoint [11] 383264 0
Baseline and 12 weeks
Secondary outcome [12] 383265 0
Markers of airway infection:
- sputum levels of cathelicidin antimicrobial peptide (LL-37)
Timepoint [12] 383265 0
Baseline and 12 weeks
Secondary outcome [13] 383266 0
Markers of airway infection:
- sputum procalcitonin
Timepoint [13] 383266 0
Baseline and 12 weeks
Secondary outcome [14] 383267 0
Markers of airway infection:
- sputum culture
Timepoint [14] 383267 0
Baseline and 12 weeks
Secondary outcome [15] 383268 0
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
Timepoint [15] 383268 0
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.

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Oral, intravenous or inhaled antibiotics within 4 weeks prior to commencing study
• Patients taking continuous macrolide therapy (for 3 months or longer) within 3 months of screening
• Patients taking continuous oral corticosteroids (for 6 weeks or longer) or immunosuppressive agents (e.g. azathioprine, methotrexate, cyclophosphamide)
• Bronchiectasis exacerbation / respiratory infection requiring oral or intravenous antibiotic treatment within 4 weeks prior to commencing study treatment
• Use of prescribed or dietary antioxidant supplement within 1 month of screening
• Body mass index <18.5 kg/m2
• Patients with a history of non-compliance with medications
• Patients with significant medical conditions other than bronchiectasis:
• Patients with cystic fibrosis
• Patients with primary ciliary dyskinesia
• Patients with hypogammaglobulinaemia or other primary or acquired immunodeficiency
• Patients with allergic bronchopulmonary aspergillosis
• Pregnant or lactating women
• Participation in a separate clinical or device trial within 4 weeks of screening
• Allergy to any components of Transmax
• Patients with evidence of active or suspected cancer

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All participants will receive resveratrol, but will receive one of two doses. There is no placebo / control arm to this study. Dose allocation will be randomised using central randomisation by computerised block randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
This is a single centre, pre-post, open-label study in patients with stable bronchiectasis, over 12 weeks.

All participants will received oral resveratrol, with the primary endpoint evaluating the effects on sputum neutrophil elastase.

Participants with be randomised to receive either 500 mg twice daily, or 1000 mg twice daily to help to determine the optimal dose of resveratrol supplementation in bronchiectasis and guide a future, larger clinical trial that will evaluate clinical end-points.

All participants will receive resveratrol for 12 weeks, with no control group. The participant and investigators will be aware of the dosage being taken.
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Associate Professor Alain Vandal (Senior Biostatistician) was involved in the sample size calculation and will perform future statistical analyses for this study. A sample size of 40 participants gives a reasonable estimate of variance in this pilot study.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/08/2020
Actual
Date of last participant enrolment
Anticipated
1/02/2021
Actual
Date of last data collection
Anticipated
26/04/2021
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment outside Australia
Country [1] 22531 0
New Zealand
State/province [1] 22531 0
Auckland

Funding & Sponsors
Funding source category [1] 305664 0
Government body
Name [1] 305664 0
Health Research Council of New Zealand
Country [1] 305664 0
New Zealand
Funding source category [2] 305922 0
Government body
Name [2] 305922 0
Counties Manukau Health
Country [2] 305922 0
New Zealand
Primary sponsor type
Government body
Name
Health Research Council of New Zealand
Address
Level 3 - ProCARE Building,
Grafton Mews,
at 110 Stanley Street,
Grafton, Auckland 1010
Country
New Zealand
Secondary sponsor category [1] 306087 0
Government body
Name [1] 306087 0
Counties Manukau Health
Address [1] 306087 0
100 Hospital Road,
Otahuhu,
Auckland,
2025
Country [1] 306087 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305585 0
Heath and Disability Ethics Committee of NZ: Central Health and Disability Ethics Committee
Ethics committee address [1] 305585 0
Ethics committee country [1] 305585 0
New Zealand
Date submitted for ethics approval [1] 305585 0
12/03/2020
Approval date [1] 305585 0
12/05/2020
Ethics approval number [1] 305585 0
20/CEN/66

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 100862 0
Dr Benjamin Diggins
Address 100862 0
Department of Respiratory Medicine
Middlemore Hospital
Counties Manukau Health
3rd Floor Esme Green Building
100 Hospital Road
Otahuhu
Auckland
2025
Country 100862 0
New Zealand
Phone 100862 0
+64 9 276 0044
Fax 100862 0
Email 100862 0
[email protected]
Contact person for public queries
Name 100863 0
Benjamin Diggins
Address 100863 0
Department of Respiratory Medicine
Middlemore Hospital
Counties Manukau Health
3rd Floor Esme Green Building
100 Hospital Road
Otahuhu
Auckland
2025
Country 100863 0
New Zealand
Phone 100863 0
+64 9 276 0044
Fax 100863 0
Email 100863 0
[email protected]
Contact person for scientific queries
Name 100864 0
Benjamin Diggins
Address 100864 0
Department of Respiratory Medicine
Middlemore Hospital
Counties Manukau Health
3rd Floor Esme Green Building
100 Hospital Road
Otahuhu
Auckland
2025
Country 100864 0
New Zealand
Phone 100864 0
+64 9 276 0044
Fax 100864 0
Email 100864 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only, after de-identification.
When will data be available (start and end dates)?
Ending 5 years following main results publication
Available to whom?
Case by case at the discretion of the investigators
Available for what types of analyses?
Meta-analyses
Only to achieve the aims in the approved proposal
How or where can data be obtained?
Access subject to approvals by Principal Investigator
- Dr Benjamin Diggins - [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7884Study protocol    379451-(Uploaded-07-05-2020-09-56-22)-Study-related document.pdf
7885Informed consent form    379451-(Uploaded-07-05-2020-09-56-02)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.