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Trial registered on ANZCTR


Registration number
ACTRN12619000861156p
Ethics application status
Submitted, not yet approved
Date submitted
30/05/2019
Date registered
18/06/2019
Date last updated
18/06/2019
Date data sharing statement initially provided
18/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A comparison of drug metabolism in healthy volunteers and patients with severe chronic obstructive lung disease (COPD)
Scientific title
Assessment of cytochrome P450 function in patients with severe COPD using a phenotyping drug cocktail
Secondary ID [1] 298372 0
Locality (Canterbury District Health Board) research number: RO# 19107
Universal Trial Number (UTN)
U1111-1229-9519
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic obstructive Pulmonary Disease (COPD) 313041 0
Drug metabolism 313043 0
Condition category
Condition code
Respiratory 311542 311542 0 0
Chronic obstructive pulmonary disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a primary pharmacokinetic study. This not a classical intervention study in that the intervention is best considered an investigation.

There are two study arms: arm 1 is 12 healthy volunteers and arm 2 is 12 patients with severe chronic obstructive pulmonary disease (COPD).
The intervention is a single oral dose of 6 drugs taken simultaneously under direct observation:
- midazolam 1mg (taken as 1mg of 1ml/mg liquid, added to 50ml water)
- dextromethorphan 30mg (taken as 30mg of 1mg/ml liquid, added to 50ml of water)
- losartan 25mg (taken as a single 25mg tablet)
- omeprazole 20mg (taken as a single 25mg tablet)
- caffeine 130mg and paracetamol 1000mg (taken as two tablets each containing 65mg caffeine and 500mg paracetamol). This is administered to both arms.

The dose is following by serial pharmacokinetic sampling of the parent drug and metabolite in plasma and urine for 8 hours. From this, the drug exposure is measured and drug metabolism extrapolated for each drug. The metabolism is compared between the two arms.
Intervention code [1] 314659 0
Diagnosis / Prognosis
Comparator / control treatment
The intervention is applied to both arms. The investigational group is patients with severe COPD (GOLD grade D) and cachexia, and the comparator group is healthy volunteers.
Control group
Active

Outcomes
Primary outcome [1] 320247 0
Area-under-the-curve (AUC) of the plasma concentration for midazolam, measured by LC-MS
Timepoint [1] 320247 0
Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Primary outcome [2] 320248 0
Area-under-the-curve (AUC) of the plasma concentration for dextromethorphan, measured by LC-MS
Timepoint [2] 320248 0
Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Primary outcome [3] 320302 0
Area-under-the-curve (AUC) of the plasma concentration of losartan, measured by LC-MS
Timepoint [3] 320302 0
Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Secondary outcome [1] 370973 0
Area-under-the-curve (AUC) of the plasma concentration of omeprazole, measured by LC-MS (primary outcome)
Timepoint [1] 370973 0
Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Secondary outcome [2] 370974 0
Area-under-the-curve (AUC) of the plasma concentration of caffeine, measured by LC-MS (primary outcome)
Timepoint [2] 370974 0
Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Secondary outcome [3] 371111 0
Oral clearance of midazolam (calculated using dose/AUC for plasma concentrations measured by LC-MS) – primary outcome
Timepoint [3] 371111 0
Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Secondary outcome [4] 371112 0
Oral clearance of dextromethorphan (calculated using dose/AUC for plasma concentrations measured by LC-MS) – primary outcome
Timepoint [4] 371112 0
Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Secondary outcome [5] 371113 0
Oral clearance of losartan (calculated using dose/AUC for plasma concentrations measured by LC-MS) – primary outcome
Timepoint [5] 371113 0
Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Secondary outcome [6] 371114 0
Oral clearance of omeprazole (calculated using dose/AUC for plasma concentrations measured by LC-MS) – primary outcome
Timepoint [6] 371114 0
Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Secondary outcome [7] 371115 0
Oral clearance of caffeine (calculated using dose/AUC for plasma concentrations measured by LC-MS) – primary outcome
Timepoint [7] 371115 0
Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Secondary outcome [8] 371116 0
Ratios of plasma and urinary midazolam and metabolite (4-OH midazolam), as measured by LC-MS
Timepoint [8] 371116 0
Plasma: Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Urine: Continual urine collection for 0-4 hours and 4-8 hours post dose (i.e. not measured as discreet time points but as block collection).
Secondary outcome [9] 371117 0
Ratios of plasma and urinary dextromethorphan and metabolite (dextrorphan), as measured by LC-MS
Timepoint [9] 371117 0
Plasma: Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Urine: Continual urine collection for 0-4 hours and 4-8 hours post dose (i.e. not measured as discreet time points but as block collection).
Secondary outcome [10] 371118 0
Ratios of plasma and urinary losartan and metabolite (E-3174), as measured by LC-MS
Timepoint [10] 371118 0
Plasma: Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Urine: Continual urine collection for 0-4 hours and 4-8 hours post dose (i.e. not measured as discreet time points but as block collection).
Secondary outcome [11] 371119 0
Ratios of plasma and urinary omeprazole and metabolite (5-OH omeprazole), as measured by LC-MS
Timepoint [11] 371119 0
Plasma: Baseline, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, and 8h post dose.
Urine: Continual urine collection for 0-4 hours and 4-8 hours post dose (i.e. not measured as discreet time points but as block collection).
Secondary outcome [12] 371120 0
Ratios of plasma and urinary caffeine and metabolite (paraxanthine), as measured by LC-MS
Timepoint [12] 371120 0
Urine: Continual urine collection for 0-4 hours and 4-8 hours post dose (i.e. not measured as discreet time points but as block collection).

Eligibility
Key inclusion criteria
Healthy volunteers:
• Age over 18 years old
• Ability to understand and the willingness to sign or verbally consent to a written or verbal informed consent document
• Ability to abstain from caffeine for 48 hours prior to the study and for the duration of the pharmacokinetic sampling
• Body mass index 18 – 30

Patients with COPD:
• COPD with GOLD D severity
• Body mass index less than or equal to 25
• Age over 18 years old
• Ability to understand and the willingness to sign or verbally consent to a written or verbal informed consent document
• Ability to abstain from caffeine for 48 hours prior to the study and for the duration of the pharmacokinetic sampling
• Ability to safely swallow tablets
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Healthy volunteers:
• Known sensitivity or contraindications to any of the cocktail drugs
• Concomitant use of any of the study medicines (except caffeine)
• Concomitant use of medicines known to be moderate or major inhibitors or inducers of cytochrome P450
• Current smoker
• Any medical condition expected to affect study drug metabolism or ability to participate in the study
• Pregnancy

Patients with COPD:
• Known sensitivity or contraindications to any of the cocktail drugs
• Concomitant use of any of the study medicines (except caffeine)
• Concomitant use of medicines known to be moderate or major inhibitors or inducers of cytochrome P450
• Current smoker
• Liver cirrhosis
• Active hepatitis
• Significant small bowel resection
• Oral corticosteroid use in the last 2 weeks
• Exacerbation of COPD in the last 2 weeks
• Intercurrent illness expected to affect study drug metabolism
• Using domiciliary oxygen
• Active malignancy
• Pregnancy

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



Intervention assignment
Other
Other design features
All participants receive the same intervention (cocktail of study drugs). Within the study groups are two cohorts of participants: healthy volunteers and patients with COPD. All receive the intervention but are analysed separately and therefore not considered a single group study.
Phase
Phase 4
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Sample sizes were primarily chosen on the basis of feasibility. These sample sizes are consistent with standard practice for pharmacokinetic studies.
Results will be analysed by plotting the plasma concentrations for each drug and each patient against time from dose to produce a concentration-time curve. The AUC will be calculated using the trapezoidal rule, and oral drug clearance calculated using dose/AUC.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2019
Actual
Date of last participant enrolment
Anticipated
2/12/2019
Actual
Date of last data collection
Anticipated
2/12/2019
Actual
Sample size
Target
24
Accrual to date
Final
Recruitment outside Australia
Country [1] 21536 0
New Zealand
State/province [1] 21536 0
Canterbury

Funding & Sponsors
Funding source category [1] 302908 0
Charities/Societies/Foundations
Name [1] 302908 0
Canterbury Medical Research Foundation
Country [1] 302908 0
New Zealand
Primary sponsor type
Individual
Name
Dr Richard McNeill
Address
Dept of Clinical Pharmacology
Christchurch Hospital
2 Riccarton Avenue
Christchurch 8011
Country
New Zealand
Secondary sponsor category [1] 302868 0
Individual
Name [1] 302868 0
Prof Matthew Doogue
Address [1] 302868 0
Dept of Clinical Pharmacology
Christchurch Hospital
2 Riccarton Avenue
Christchurch 8011
Country [1] 302868 0
New Zealand
Other collaborator category [1] 280719 0
Individual
Name [1] 280719 0
Dr Alex Cole
Address [1] 280719 0
Christchurch Clinical Studies Trust
Level 4/264 Antigua St
Christchurch Central
Christchurch 8011
Country [1] 280719 0
New Zealand
Other collaborator category [2] 280720 0
Individual
Name [2] 280720 0
Dr Michael Epton
Address [2] 280720 0
Dept of Respiratory Medicine
Christchurch Hospital
2 Riccarton Avenue
Christchurch 8011
Country [2] 280720 0
New Zealand

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 303480 0
Health and Disability Ethics Committee
Ethics committee address [1] 303480 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 303480 0
New Zealand
Date submitted for ethics approval [1] 303480 0
17/06/2019
Approval date [1] 303480 0
Ethics approval number [1] 303480 0

Summary
Brief summary
The cytochrome P450 (CYP) superfamily is the main group of enzymes responsible for drug metabolism. There are 5 main enzymes which metabolise the majority of drugs. Their function can be measured in vivo with drug probes. Drug cocktails are several probes simultaneously administered to measure several enzymes simultaneously. The Inje drug cocktail uses a single dose of midazolam, dextromethorphan, omeprazole, losartan and caffeine to measure the five main CYP enzymes.

Disease states including hypoxia, cachexia and heart failure are known to affect CYP function but the effect on individual enzymes is unknown. The effect of severe COPD as a clinical phenotype is unknown.

We aim to use a modification of the Inje cocktail, including paracetamol, to measure CYP function in patients with severe COPD and compare this to healthy volunteers. The primary outcomes will be oral drug clearance and area-under-the-curve of the concentration-time curve for each study drug.

We hypothesise that COPD will inhibit many or all of the studied CYP enzymes and this information can be used to optimise drug dosing in this population.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93798 0
Dr Richard McNeill
Address 93798 0
Dept of clinical pharmacology
Christchurch Hospital
2 Riccarton Avenue
Christchurch 8011
Country 93798 0
New Zealand
Phone 93798 0
+64 33641858
Fax 93798 0
Email 93798 0
[email protected]
Contact person for public queries
Name 93799 0
Richard McNeill
Address 93799 0
Dept of clinical pharmacology
Christchurch Hospital
2 Riccarton Avenue
Christchurch 8011
Country 93799 0
New Zealand
Phone 93799 0
+64 33641858
Fax 93799 0
Email 93799 0
[email protected]
Contact person for scientific queries
Name 93800 0
Richard McNeill
Address 93800 0
Dept of clinical pharmacology
Christchurch Hospital
2 Riccarton Avenue
Christchurch 8011
Country 93800 0
New Zealand
Phone 93800 0
+64 33641858
Fax 93800 0
Email 93800 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Pooled data will be publicly available


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseDrug metabolism in severe chronic obstructive pulmonary disease: A phenotyping cocktail study.2021https://dx.doi.org/10.1111/bcp.14862
N.B. These documents automatically identified may not have been verified by the study sponsor.