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Trial registered on ANZCTR


Registration number
ACTRN12613001112752
Ethics application status
Approved
Date submitted
28/09/2013
Date registered
3/10/2013
Date last updated
18/07/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of broccoli consumption on the activity of drug metabolising enzymes in people of European and South Asian ancestry
Scientific title
The effect of broccoli consumption on the activity of drug metabolising enzymes in people of European and South Asian ancestry
Secondary ID [1] 283210 0
Nil
Universal Trial Number (UTN)
U1111-1147-9630
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Altered drug-metabolising enzyme activity (CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4) in people of European and South Asian ancestry. 290209 0
Condition category
Condition code
Other 290602 290602 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Broccoli-enriched diet (200 g of microwave-steamed broccoli with lunch and dinner) for 6 days (Days 3-8).

Two food diaries will be used to monitor adherence to the diet. Furthermore, phenethyl isothiocyanate (a broccoli constituent responsible for changes in CYP-enzyme activity) will be detected in participant plasma using an HPLC assay.

Five drugs will be administered as CYP-isoform-selective probes to assess enzyme activity. On study days, participants will receive 100 mg caffeine (CYP1A2), 20 mg omeprazole (CYP2C19), 25 mg losartan (CYP2C9), 30 mg dextromethorphan (CYP2D6) and 2 mg midazolam (CYP3A4) in 5% dextrose solution. All medicines will be administered orally.

The phenotyping cocktail will be administered before (Day 1), concomitantly with (Day 2) and 6 days after a broccoli-enriched diet (Day 9). Please note, the broccoli-enriched diet is administered for 6 days from Days 3-8 (inclusive) with a single 200 g amount concomitantly administered with the cocktail on Day 2.
Intervention code [1] 288042 0
Treatment: Other
Comparator / control treatment
Prospective, sequential design; each participant is their own control i.e. before broccoli-enriched diet versus after broccoli-enriched diet
Control group
Uncontrolled

Outcomes
Primary outcome [1] 290620 0
Activity of CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4 as per the below metrics. CYP-isoform-specific probe-drug concentrations will be measured using a previously-validated LC-MS/MS assay.

Please note that this is not a composite primary outcome but five discreet, independent study endpoints.

CYP1A2: Ratio of paraxanthine to caffeine plasma concentrations (micromol/L) at 4 hours post-dose
CYP2C19: Ratio of 5-hydroxyomeprazole to omeprazole plasma concentrations (nmol/L) at 4 or 6 hours post-dose (at 4 hours if detectable otherwise at 6 hours)
CYP2C9: Ratio of EXP-3174 AUC0-6h to losartan AUC0-6h
CYP2D6: Ratio of dextrorphan AUC0-6h to dextromethorphan AUC0-6h
CYP3A4: Ratio of 1’-hydroxymidazolam AUC0-6h to midazolam AUC0-6h

If the distribution of CYP isoform activities is normal then a paired t-test will be used to test these hypotheses at a significance level of p = 0.05. In the case that the distribution of CYP isoform activities is not normal the non-parametric Wilcoxon Signed-Rank test will be performed instead.
Timepoint [1] 290620 0
On Day 1 (baseline), Day 2 (short-term broccoli condition) and Day 9 (medium-term broccoli condition) at 0, 1, 2, 4 and 6 h post-dose of the CYP phenotyping cocktail.
Secondary outcome [1] 304921 0
Difference in CYP isoform activities between people of European and South Asian ancestry.

Activity of CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4 as per the below metrics. CYP-isoform-specific probe-drug concentrations will be measured using a previously-validated LC-MS/MS assay.

Please note that this is not a composite secondary outcome but five discreet, independent study endpoints.

CYP1A2: Ratio of paraxanthine to caffeine plasma concentrations (micromol/L) at 4 hours post-dose
CYP2C19: Ratio of 5-hydroxyomeprazole to omeprazole plasma concentrations (nmol/L) at 4 or 6 hours post-dose (at 4 hours if detectable otherwise at 6 hours)
CYP2C9: Ratio of EXP-3174 AUC0-6h to losartan AUC0-6h
CYP2D6: Ratio of dextrorphan AUC0-6h to dextromethorphan AUC0-6h
CYP3A4: Ratio of 1’-hydroxymidazolam AUC0-6h to midazolam AUC0-6h

If the distribution of CYP isoform activities is normal then a paired t-test will be used to test these hypotheses at a significance level of p = 0.05. In the case that the distribution of CYP isoform activities is not normal the non-parametric Wilcoxon Signed-Rank test will be performed instead.
Timepoint [1] 304921 0
On Day 1 (baseline), Day 2 (short-term broccoli condition) and Day 9 (medium-term broccoli condition) at 0, 1, 2, 4 and 6 h post-dose of the CYP phenotyping cocktail.

Eligibility
Key inclusion criteria
i. Male, aged 18-55 years
ii. European or South Asian geographic ancestry
iii. Non-smoker or ex-smoker that has abstained from smoking for at least 6 months
iv. Ability to comply with the planned procedures and provide written informed consent
which requires a level of English language competency to effectively understand the
protocol and adequately meet the definition of informed consent
v. Self-reported healthy with no reported or diagnosed acute or chronic health conditions
vi. Access to a microwave with an appropriate cooking setting
Minimum age
18 Years
Maximum age
55 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
i. Known hypersensitivity or intolerance to any of the five drugs used in the study
ii. History of clinical signs of hypotension, specifically fainting, light-headedness and/or a blood pressure lower than 80/60 mmHg
iii. Female
iv. Known food allergies or intolerances that limit participation in this study
v. Oral antimicrobial use within the past 3 months
vi. Body mass index (BMI) outside of 18.5-28.0 kg.m-2
vii. Currently taking or using any prescription, OTC, complementary or illicit medicines
viii. Recently given blood or recently involved in another clinical study in the last 3 months

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
n/a
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Participants act as their own control (baseline 'everyday' diet versus post-dietary intervention) in a sequential design.
Phase
Not Applicable
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Endpoints (CYP activity metrics) will be natural-log-transformed and analysed using a linear mixed-effects model as per recent studies utilising a phenotyping cocktail approach. This technique has demonstrated suitability for analysing crossover, repeat-measures data of this nature. Least-squares means and standard errors of the differences between endpoints across study days will be log-back-transformed and presented as geometric mean ratios with 90% confidence intervals (p = 0.1) as in recently published studies.

While the variability of CYP activity varies between isoforms, CYP1A2 is recognised as having one of the highest inter-subject variabilities. Further, multiple studies performed by our research group have focused on this isoform and as such, robust data are available for more accurate assessments of its variability in this study's target populations.

A sample size calculation has been performed with guidance from a biostatistician using the GLIMMPSE sample size calculator for crossover studies with repeat-measures found at http://glimmpse.samplesizeshop.org. At 80% power with a standard deviation of 0.3 (from the literature and our group's previous research) a total sample size of n = 12 (n = 6 in each ancestry group) is required to detect a difference of up to 25% in the primary endpoint with an alpha of 0.1 (90% confidence interval approach commonly used in studies of this nature).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
21/10/2013
Actual
21/10/2013
Date of last participant enrolment
Anticipated
31/08/2016
Actual
12/09/2016
Date of last data collection
Anticipated
Actual
28/09/2016
Sample size
Target
12
Accrual to date
Final
21
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 1567 0
Concord Repatriation Hospital - Concord
Recruitment postcode(s) [1] 7392 0
2139 - Concord Repatriation Hospital

Funding & Sponsors
Funding source category [1] 288058 0
University
Name [1] 288058 0
University of Sydney - Peter Coates Postgraduate Scholarship in Ethnopharmacology
Country [1] 288058 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
The University of Sydney
NSW 2006
Australia
Country
Australia
Secondary sponsor category [1] 291769 0
None
Name [1] 291769 0
Address [1] 291769 0
Country [1] 291769 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289983 0
Sydney Local Health District HREC (CRGH)
Ethics committee address [1] 289983 0
Ethics committee country [1] 289983 0
Australia
Date submitted for ethics approval [1] 289983 0
22/11/2012
Approval date [1] 289983 0
04/04/2013
Ethics approval number [1] 289983 0
HREC/12/CRGH/206

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

Contacts
Principal investigator
Name 42922 0
Mr Shane K Eagles
Address 42922 0
Attn: Shane Eagles
Building 4 (ANZAC 3)
Concord Repatriation General Hospital
Hospital Rd
CONCORD NSW 2139
Country 42922 0
Australia
Phone 42922 0
+61431635958
Fax 42922 0
+61297678069
Email 42922 0
[email protected]
Contact person for public queries
Name 42923 0
Shane K Eagles
Address 42923 0
Attn: Shane Eagles
Building 4 (ANZAC 3)
Concord Repatriation General Hospital
Hospital Rd
CONCORD NSW 2139
Country 42923 0
Australia
Phone 42923 0
+61431635958
Fax 42923 0
+61297678069
Email 42923 0
[email protected]
Contact person for scientific queries
Name 42924 0
Shane K Eagles
Address 42924 0
Attn: Shane Eagles
Building 4 (ANZAC 3)
Concord Repatriation General Hospital
Hospital Rd
CONCORD NSW 2139
Country 42924 0
Australia
Phone 42924 0
+61431635958
Fax 42924 0
+61297678069
Email 42924 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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