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Trial registered on ANZCTR


Registration number
ACTRN12621001042831
Ethics application status
Approved
Date submitted
5/07/2021
Date registered
9/08/2021
Date last updated
9/08/2021
Date data sharing statement initially provided
9/08/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Micronutrient Interactions: A Pharmacokinetics Study
Scientific title
Investigation of a broad-spectrum micronutrient formulation as a possible perpetrator of pharmacokinetic micronutrient-drug interactions in healthy adults
Secondary ID [1] 304697 0
None known
Universal Trial Number (UTN)
U1111-1230-6018
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
anxiety 322687 0
depression 322688 0
Condition category
Condition code
Mental Health 320296 320296 0 0
Anxiety
Mental Health 320297 320297 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Healthy volunteers will take a drug 'cocktail' by mouth (100mg caffeine, 25mg losartan, 20mg omeprazole, 30mg dextromethorphan syrup diluted in 50ml of plain water, 2mg midazolam in 50ml water) on two occasions. The first time will be in the absence of broad spectrum micronutrients. The second time will be in the presence of steady state broad spectrum micronutrients (after 13 days consumption). Adherence will not be monitored.

For broad spectrum micronutrients to be at steady state, they will be consumed for 13 days; initially at 1 tablet three times daily increasing by 3 tabs (in divided doses) every second day until 4 tabs three times daily is reached. Broad spectrum micronutrients will be supplied by Hardy Nutritionals in the form of Daily Essential Nutrients. Daily Essential Nutrients are a complex mix of vitamins and minerals. There are more than 30 constituent ingredients including vitamins A,C,D,E,K and minerals Calcium, Iron, Phosphorus, and Magnesium.
Intervention code [1] 321076 0
Treatment: Drugs
Comparator / control treatment
Participants will act as their own controls. Plasma levels of the drug 'cocktail' will be measured in the absence and then the presence of broad spectrum micronutrients.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328152 0
Serum concentrations over time will be used to construct a concentration-time curve for caffeine 100mg; both in the absence of and in the presence of steady state micronutrients.

The area under the curve from time 0 – infinity (AUC0-t) for caffeine will be calculated using the trapezoidal rule. The change in AUC for each patient will be evaluated using a paired t-test.

The primary outcome will be expressed as the ratio of the geometric means for the AUC for caffeine, with / without micronutrients.
Timepoint [1] 328152 0
Repeated serum concentrations at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h following ingestion of caffeine will be used to create a concentration-time curve.
Primary outcome [2] 328521 0
Serum concentrations over time will be used to construct a concentration-time curve for losartan 25mg; both in the absence of and in the presence of steady state micronutrients.

The area under the curve from time 0 – infinity (AUC0-t) for losartan will be calculated using the trapezoidal rule. The change in AUC for each patient will be evaluated using a paired t-test.

The primary outcome will be expressed as the ratio of the geometric means for the AUC for losartan, with / without micronutrients.
Timepoint [2] 328521 0
Repeated serum concentrations at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h following ingestion of losartan will be used to create a concentration-time curve.
Primary outcome [3] 328522 0
Serum concentrations over time will be used to construct a concentration-time curve for omeprazole 20mg; both in the absence of and in the presence of steady state micronutrients.

The area under the curve from time 0 – infinity (AUC0-t) for omeprazole will be calculated using the trapezoidal rule. The change in AUC for each patient will be evaluated using a paired t-test.

The primary outcome will be expressed as the ratio of the geometric means for the AUC for omeprazole, with / without micronutrients.
Timepoint [3] 328522 0
Repeated serum concentrations at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h following ingestion of omeprazole will be used to create a concentration-time curve.
Secondary outcome [1] 397850 0
Depression Anxiety Stress Scale-21 (DASS)
Timepoint [1] 397850 0
Baseline, 2 weeks (after steady state micronutrients)
Secondary outcome [2] 397851 0
Warwick-Edinburgh Mental Well-being Scale
Timepoint [2] 397851 0
Baseline, 2 weeks post commencement (once steady state micronutrients has been achieved)
Secondary outcome [3] 397852 0
Abbreviated Profile of Mood States Questionnaire
Timepoint [3] 397852 0
Baseline, 2 weeks post commencement (once steady state micronutrients has been achieved)
Secondary outcome [4] 397853 0
Sleep Quality Scale
Timepoint [4] 397853 0
Baseline, 2 weeks post commencement (once steady state micronutrients has been achieved)
Secondary outcome [5] 397854 0
The Life Satisfaction Scale
Timepoint [5] 397854 0
Baseline, 2 weeks post commencement (once steady state micronutrients has been achieved)
Secondary outcome [6] 397855 0
The Side-Effect Checklist (based on the Antidepressant Side-Effect Checklist)
Timepoint [6] 397855 0
Baseline, 2 weeks post commencement (once steady state micronutrients has been achieved)
Secondary outcome [7] 399324 0
This is a further primary outcome measure
Serum concentrations over time will be used to construct a concentration-time curve for 30mg dextromethorphan syrup; both in the absence of and in the presence of steady state micronutrients.

The area under the curve from time 0 – infinity (AUC0-t) for dextromethorphan will be calculated using the trapezoidal rule. The change in AUC for each patient will be evaluated using a paired t-test.

The primary outcome will be expressed as the ratio of the geometric means for the AUC for dextromethorphan, with / without micronutrients.
Timepoint [7] 399324 0
Repeated serum concentrations at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h following ingestion of dextromethorphan will be used to create a concentration-time curve.
Secondary outcome [8] 399325 0
This is a further primary outcome measure
Serum concentrations over time will be used to construct a concentration-time curve for 2mg midazolam; both in the absence of and in the presence of steady state micronutrients.

The area under the curve from time 0 – infinity (AUC0-t) for midazolam will be calculated using the trapezoidal rule. The change in AUC for each patient will be evaluated using a paired t-test.

The primary outcome will be expressed as the ratio of the geometric means for the AUC for midazolam, with / without micronutrients.
Timepoint [8] 399325 0
Repeated serum concentrations at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h following ingestion of midazolam will be used to create a concentration-time curve.

Eligibility
Key inclusion criteria
Healthy volunteers
Normal vital signs
ECG normal
On no regular medication
DASS (a measure of anxiety, depression, and stress) in normal range)
Not pregnant
Minimum age
18 Years
Maximum age
50 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Taking any regular medication including prescribed, over-the-counter, complementary and alternative medicines and recreational substances during the week prior to and for the duration of the study. Paracetamol will be permitted except during the clinic visit days.
• Current smoker.
• Consumption of large amounts of cruciferous vegetables during the 2 weeks prior to and for duration of study (cruciferous vegetables are CYP1A2 inducers).
• Consumption of grapefruit juice for 48h before and for the duration of the study.
• Prior adverse reaction to any of the drugs used in the study.

Study design
Purpose of the study
Treatment
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 design features
Single centre open-label study of healthy volunteers
Phase
Not Applicable
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis
The primary outcome will be the Area Under Curve with micronutrients / Area Under Curve without micronutrients.

Secondary outcome measures will be compared to the same measures at baseline using paired T-tests

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 23942 0
New Zealand
State/province [1] 23942 0
Canterbury

Funding & Sponsors
Funding source category [1] 309064 0
Charities/Societies/Foundations
Name [1] 309064 0
The Calgary Foundation
Address [1] 309064 0
1180 – 105 12 Avenue SE
Calgary, AB T2G 1A1
Alberta
Canada
Country [1] 309064 0
Canada
Primary sponsor type
University
Name
University of Otago
Address
University of Otago
Research and Enterprise
Centre for Innovation, Level 1 (East Wing),
87 St David St,
Dunedin 9012
Country
New Zealand
Secondary sponsor category [1] 310012 0
None
Name [1] 310012 0
Address [1] 310012 0
Country [1] 310012 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308942 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 308942 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 308942 0
New Zealand
Date submitted for ethics approval [1] 308942 0
Approval date [1] 308942 0
01/07/2021
Ethics approval number [1] 308942 0
21/CEN/132

Summary
Brief summary
Broad spectrum micronutrient formulations are combinations of vitamins and minerals that can be used for treatment purposes. There is emerging evidence for the use of these formulations to treat anxiety, depression and other mental disorders. The majority of studies evaluating broad spectrum micronutrients have done so as a primary treatment (not added to conventional psychiatric medications). These studies have produced promising results and have shown that broad spectrum micronutrient formulas are well tolerated and do not appear to cause toxicity (abnormal physical findings or blood tests).

The safety and effectiveness of combination use of broad spectrum micronutrient formulations and medications has not been formally evaluated in studies. This is a significant gap. Product databases provide preliminary data on the experience of children and adults taking broad spectrum micronutrient formulations while on antidepressant and other medications. These databases suggest that broad spectrum micronutrient formulations can be combined satisfactorily psychiatric medication although it is recommended to introduce micronutrients slowly and review psychiatric medication regularly due to expert opinion suggesting that micronutrients may increase the levels of antidepressants. It is important to clarify if there are interactions between broad spectrum micronutrient formulations and psychiatric medication in order for clarity on whether they can be taken in combination. If they are safe in combination, there will be further questions about whether or not clinical outcomes are improved by combination treatment.

In order to clarify whether or not broad spectrum micronutrients interact with standard medications, and as an initial step prior to clarifying whether or not treatment with combination broad spectrum micronutrients and psychiatric medication improves the outcome of psychiatric disorders, a study testing for common broad spectrum micronutrient-drug interactions is required.

We therefore propose to study broad spectrum micronutrient-drug interactions through the use of standard drug-interaction methodology. We hypothesise that there will not be significant interactions between commonly prescribed medications and broad spectrum micronutrients.

Our study involves measurement of serum drug concentrations in healthy volunteers following ingestion of a ‘cocktail’ containing 5 medicines, each metabolised by different enzyme pathways. This testing will be done twice, before and after two weeks of regular daily micronutrients. If the serum concentrations of any of the 5 probe drugs are significantly changed by taking micronutrients, this is consistent with a pharmacokinetic drug interaction. This is essential information to inform prescribers about the use of combinations of broad spectrum micronutrients and medication, and to inform risk assessments for any future clinical studies of broad spectrum micronutrient formulations.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112410 0
Dr Ben Beaglehole
Address 112410 0
Department of Psychological Medicine
University of Otago, Christchurch
PO Box 4345
Christchurch Mail Centre
Christchurch 8140
Country 112410 0
New Zealand
Phone 112410 0
+64 0272127488
Fax 112410 0
+6433720407
Email 112410 0
ben.beaglehole@otago.ac.nz
Contact person for public queries
Name 112411 0
Dr Ben Beaglehole
Address 112411 0
Department of Psychological Medicine
University of Otago, ChristchurchPO Box 4345
Christchurch Mail Centre
Christchurch 8140
Country 112411 0
New Zealand
Phone 112411 0
+64 0272127488
Fax 112411 0
+6433720407
Email 112411 0
ben.beaglehole@otago.ac.nz
Contact person for scientific queries
Name 112412 0
Dr Ben Beaglehole
Address 112412 0
Department of Psychological Medicine
University of Otago, ChristchurchPO Box 4345
Christchurch Mail Centre
Christchurch 8140
Country 112412 0
New Zealand
Phone 112412 0
+64 0272127488
Fax 112412 0
+6433720407
Email 112412 0
ben.beaglehole@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Given the small study size we do not wish to share data that may identify individual participants
What supporting documents are/will be available?
No other documents available
Summary results
No Results