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Trial registered on ANZCTR


Registration number
ACTRN12617001647325
Ethics application status
Approved
Date submitted
14/11/2017
Date registered
21/12/2017
Date last updated
4/02/2020
Date data sharing statement initially provided
5/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A micronutrient intervention for adults experiencing symptoms of anxiety and depression.
Scientific title
An investigation examining the effectiveness and safety of a micronutrient intervention on symptoms of depression and anxiety adults: A double blind, randomized, placebo controlled trial.
Secondary ID [1] 293131 0
NIL
Universal Trial Number (UTN)
U111111994026
Trial acronym
NoMAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anxiety 305193 0
Depression 305194 0
Condition category
Condition code
Mental Health 304509 304509 0 0
Anxiety
Mental Health 304510 304510 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Micronutrient formula
Participants will be randomly assigned to receive either a micronutrient formula or a placebo for ten weeks. After ten weeks, all participants will enter into an open-label phase whereby all participants can choose to take the micronutrient formula for another 10 weeks. Both the micronutrient formula and the placebo are in capsule form and are to be taken orally at a dose of 12 capsules per day; four capsules taken three times per day with food and water. The micronutrient intervention is a blend of vitamins, minerals, antioxidants and amino acids. The formula, Daily Essential Nutrients, is being manufactured and donated by Hardy Nutritionals (Registered Trademark), Canada and consists of the following ingredients. The following doses are for 12 capsules (full dose per day): Vitamin A (as retinyl palmitate), 5,760 IU; Vitamin C (as ascorbic acid), 600 mg; Vitamin D (as cholecalciferol), 3,000 IU; Vitamin E (as d-alpha tocopheryl succinate), 360 IU; Vitamin K (75% as phylloquinone; 25% as menaquinone-7), 120 mcg; Thiamin (as thiamin mononitrate), 60 mg; Riboflavin, 18 mg; Niacin (as niacinamide), 90 mg; Vitamin B6 (as pyridoxine hydrochloride), 69.9 mg; Folate (as L-methylfolate calcium), 801 mcg; Vitamin B12 (as methylcobalamin), 900 mcg; Biotin, 1080 mcg; Pantothenic acid (as d-calcium pantothenate), 30 mg; Calcium (as chelate), 1,320 mg; Iron (as chelate), 13.8 mg; Phosphorus (as chelate), 840 mg; Iodine (as chelate), 204 mcg; Magnesium (as chelate), 600 mg; Zinc (as chelate), 48 mg; Selenium (as chelate), 204 mcg; Copper (as chelate), 7.2 mg; Manganese (as chelate), 9.6 mg; Chromium (as chelate), 624 mcg; Molybdenum (as chelate), 144 mcg; Potassium (as chelate), 240 mg. Proprietary blend: Choline bitartrate, Alpha-lipoic acid, Mineral wax, Inositol, Acetyl-L-carnitine, Grape seed extract, Ginkgo biloba leaf extract, L-methionine, N-acetyl-L-cysteine, Boron, Vanadium, Lithium orotate, Nickel. Other ingredients: Vegetarian capsule (hypromellose), microcrystalline cellulose, magnesium stearate, silicon dioxide, titanium dioxide.
Adherence to the intervention will be assessed weekly throughout the study period. Participants are required to report the number of capsules missed over a two or four week period and photograph unused or missed capsules, submitting photos to the study website.
Intervention code [1] 299452 0
Treatment: Other
Comparator / control treatment
Placebo group
The placebo is manufactured and donated by Hardy Nutritionals (Registered Trademark), Canada and consists of the following ingredients taken orally at a dose of 12 capsules per day; four capsules taken three times per day with food and water. The following doses are for 12 capsules: Riboflavin, 1.2g; Fiber Acacia gum, 3,600mg; Maltodextrin, 4,750.8mg; Cocoa Powder, 4mg.

Riboflavin is known to change the colour of urine and has been added to the placebo so that both the intervention and control group experience the same change in urine colour. Adding riboflavin to the placebo will ensure the blind is maintained.
Control group
Placebo

Outcomes
Primary outcome [1] 303749 0
Generalised Anxiety Disorder 7-Question Scale (GAD-7)
Timepoint [1] 303749 0
Baseline (week 0), weekly during RCT (week 1 through 10) and open label (week 11 through 20), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52).

End of RCT (week 10) is considered the primary endpoint
Primary outcome [2] 303751 0
Patient Health Questionnaire - 9 (PHQ-9)
Timepoint [2] 303751 0
Baseline (week 0), weekly during RCT (week 1 through 10) and open label (week 11 through 20), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52).

End of RCT (week 10) is considered the primary endpoint
Primary outcome [3] 303752 0
Clinical Global Inventory (CGI).
Timepoint [3] 303752 0
End of RCT (week 10), end of open label (week 20), 1 year follow up (week 52). End of RCT (week 10) is considered the primary endpoint.
Secondary outcome [1] 340071 0
Modified Clinical Global Impression (MCG-I)
Timepoint [1] 340071 0
Weekly during RCT (week 1 through 10) and open label (week 11 through 20), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52).
Secondary outcome [2] 340073 0
Depression, Anxiety and Stress Scale (DASS-21)
Timepoint [2] 340073 0
Baseline (week 0), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52)

Secondary outcome [3] 340074 0
Social Phobia Inventory (SPIN)
Timepoint [3] 340074 0
Baseline (week 0), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52)
Secondary outcome [4] 340075 0
Yale-Brown Obsessive Compulsive Scale (Y-BOCS)
Timepoint [4] 340075 0
Baseline (week 0), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52)


Secondary outcome [5] 340076 0
Panic Disorder Severity Scale (PDSS)
Timepoint [5] 340076 0
Baseline (week 0), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52)

Secondary outcome [6] 340077 0
Impact of Events Scale - Revised (IES-R)
Timepoint [6] 340077 0
Baseline (week 0), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52)

Secondary outcome [7] 340078 0
Health Anxiety Inventory (HAI)
Timepoint [7] 340078 0
Baseline (week 0), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52)


Secondary outcome [8] 340079 0
Leeds Dependence Questionnaire (LDS)
Timepoint [8] 340079 0
Baseline (week 0), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52)

Secondary outcome [9] 340081 0
Quality of Life Scale (QOLS)
Timepoint [9] 340081 0
Baseline (week 0), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52)

Secondary outcome [10] 340523 0
Dietary Screening Tool (DST)
Timepoint [10] 340523 0
Baseline (week 0), end of RCT (week 10), end of open label (week 20), 1 year follow up (week 52)


Secondary outcome [11] 340524 0
Adverse events.. Participant self-report of physical symptoms which may be attributed to the micronutrient intervention.

Adverse events will be monitored closely and participants experiencing any adverse events will be reviewed by the study physician. Follow ups will be conducted to review any participants discontinued from the trial for any reason. Safety information regarding micronutrients generally and DEN more specifically are promising. The most common adverse effects of micronutrient intervention include nausea and headaches. These difficulties can be avoided or reduced by slow titration of DEN and taking the capsules on a full stomach, which will be clearly indicated to participants.
Timepoint [11] 340524 0
Baseline (week 0), weekly during RCT (week 1 through 10) and open label (week 11 through 20), end of RCT (week 10), end of open label (week 20).

Baseline data will be collected to measure any physical symptoms experienced prior to starting intervention in order to control for commonly experienced physical symptoms that may not be associated with the intervention. This will assist in ascertaining whether or not a physical symptom could be considered an adverse event.

Treatment-emergent adverse events and risk events from the double-blind phase will be individually listed by randomized group, indicating the preferred term, date of onset, date resolved, severity, relatedness, frequency, action taken in relation to study medication and whether the adverse event is serious. The incidence of more common adverse events (greater than 5%) or adverse events of special interest may also be summarized for each randomized group.



Eligibility
Key inclusion criteria
1) between 18 and 65 years, 2) regular access to the internet, 3) considered reliable and compliant with the protocol (including the ingestion of as many as 12 capsules/day with food), 4) be proficient in comprehension of written and spoken English language and 5) and be presenting to their general practitioner (GP) with functionally impairing anxiety or depressive symptoms which cannot be better accounted for by a medical condition.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) The main strict contraindications are metabolic conditions such as Wilson’s disease (copper), haemochromatosis (iron), phenylketonuira (phenylalanine) and trimethylaminuria (choline). 2) Neurological disorders involving brain or other central function (e.g., intellectual disability, autism spectrum disorder, epilepsy, MS, narcolepsy) or other major psychiatric condition requiring hospitalization (e.g. significant mood disorder with associated suicidality, substance dependence or psychosis), 3) Any serious medical condition, 4) Any patient known to be allergic to the ingredients of the intervention, 5) Any other medication with primarily central nervous system activity, including psychotropic medication (e.g. SSRIs, tricyclics, benzodiazepines). Participants must have been off of these medications for a minimum of four weeks prior to the trial. Participants are not encouraged to come off of a medication in order to participate in the trial. 6) Women who are pregnant or breastfeeding.

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)
Sealed opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation sequence will be computer-generated by an independent researcher using the website: http://www.randomization.com and will be arranged in a 1:1 ratio using blocks.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Anxiety and depressive disorders are the most prevalent mental health issues in New Zealand, both in regards to lifetime and point prevalence rates (Te Rau Hinengaro: The New Zealand Mental Health Survey, 2006). Population estimates for the Canterbury region are approximately 500,000 people aged 15 years and above as of 2016 (Statistics New Zealand). Potential rates of depression and anxiety over the past twelve months indicate that a possible 75,000 adults in Canterbury may be experiencing an anxiety disorder and 40,000 adults may be experiencing depression and would therefore be potentially eligible for this trial (Te Rau Hinengaro: The New Zealand Mental Health Survey, 2006).

An effect size of d=0.6 was chosen based on previous research. Assuming an effect size of d=0.6, the total number of participants required would be 90 (45 in each group). Attrition rates in nutrition RCTs appear to range between 3% to 19% (Gariballa & Forster, 2007; Kaplan, Rucklidge, Romijn, & Dolph, 2015; J. J. Rucklidge et al., 2012). However, general treatment RCTs have demonstrated attrition rates ranging between 0.8% and 48%, with varying degrees of attrition linked to differences in trial design and outcome e.g. face-to-face assessment or treatment, web-based treatment, severity of adverse events (Dumville, Torgerson, & Hewitt, 2006; Hewitt, Kumaravel, Dumville, & Torgerson, 2010; Mann et al., 2013). Given the reduced face-to-face follow up, this study will allow for an anticipated 50% attrition rate. The adjusted number per treatment condition would be 68. The total sample size therefore would be 136. However, to randomise in blocks of four and to allow for excess attrition given the reduced face-to-face contact during the trial, the study will aim to recruit 200 participants, 100 in the treatment arm and 100 in the control arm.

For purposes of group statistical inference, data will be analysed first on an intention-to-treat basis using the last observation carried forward method and second on a per-protocol analysis that includes those who complied with and completed the protocol.


For the primary outcomes (GAD-7 and PHQ-9), the repeated measures of the outcome variables will be modelled using generalized linear mixed effects regression models. These models will permit the testing of differences between the micronutrient group and the placebo group over the course of the trial. Baseline scores on the primary outcome measures will be used as a covariate factors, as well as measures of demographic characteristics. For secondary outcomes (all other psychometrics), linear mixed effects models will also be used. For data from randomized trials, this modelling procedure allows the researcher to fit individual-specific slopes and intercept terms, which can account for individual variability in treatment response more precisely than methods based on Analysis of Variance. The statistical test for differences between groups will be an F test.

The pooled mean scores (and standard deviations) over the course of the trial on each of the primary outcomes will be used to compute estimates of effect size (Cohen’s d).

For secondary outcomes (all other psychometrics), linear mixed effects models will also be used, to explore the relationship between other psychiatric difficulties and the micronutrient intervention.

As a first step in determining the clinical significance of the outcomes on primary and secondary variables the Reliable Change Index will be determined for each measure using the best available psychometric norm data for the measure. Changes must exceed the relevant RCI before clinical significance of the outcome is addressed. Clinically differences between groups will be determined using cut-off scores from clinical and non-clinical population distributions (means and standard deviations) for the PHQ-9 from the clinical pre-treatment scores of the current study and the non-clinical distribution and estimate of internal reliability from the original PHQ-9 validation study. The same calculations will be used to calculate these criteria for the GAD-7. Clinical means and standard deviations will be taken from the current dataset, and non- clinical distribution values and estimates of internal reliability will be taken from the original validation study of the GAD7.

Patterns of change over time within and between groups will be further examined at the individual as well as the group level using modified Brinley Plots. These plots permit the simultaneous display of the extent of each individual’s change over time on each measure within the context of the RCI boundaries (making both improvement and deterioration available to inspection) supplemented by information about group means and the 95% Confidence Intervals (95%CI) of the means at each time point. The Concordance Correlation Coefficient will also be used to compare the extent of change produced by the treatment relative to the placebo on each measure.

Treatment-emergent adverse events and risk events from the double-blind phase will be individually listed by randomized group, indicating the preferred term, date of onset, date resolved, severity, relatedness, frequency, action taken in relation to study medication and whether the adverse event is serious. The incidence of more common adverse events (greater than 5%) or adverse events of special interest may also be summarized for each randomized group.


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] 9310 0
New Zealand
State/province [1] 9310 0
Canterbury

Funding & Sponsors
Funding source category [1] 297757 0
University
Name [1] 297757 0
University of Canterbury Department of Psychology Research Funds
Address [1] 297757 0
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country [1] 297757 0
New Zealand
Funding source category [2] 297828 0
Charities/Societies/Foundations
Name [2] 297828 0
University of Canterbury Foundation- donations given to the principal investigator
Address [2] 297828 0
University of Canterbury
Private Bag 4800,
Christchurch 8140
Country [2] 297828 0
New Zealand
Funding source category [3] 297829 0
Charities/Societies/Foundations
Name [3] 297829 0
Canterbury Medical Research Foundation
Address [3] 297829 0
Canterbury Medical Research Foundation
Level 1/230 Antigua Street
Christchurch 8011
Country [3] 297829 0
New Zealand
Funding source category [4] 297830 0
Commercial sector/Industry
Name [4] 297830 0
Hardy Nutritionals (Registered Trademark)
Address [4] 297830 0
Hardy Nutritionals (Registered Trademark)
69B Broadway Street North
PO Box 919
Raymond, Alberta
Canada T0K 2S0

Hardy's only provided the product and placebo for free, they do not directly grant funds to the project.
Country [4] 297830 0
Canada
Funding source category [5] 301858 0
Charities/Societies/Foundations
Name [5] 301858 0
The New Zealand Psychological Society, Institute of Clinical Psychology
Address [5] 301858 0
PO Box 10536
The Terrace
Wellington 6143
Country [5] 301858 0
New Zealand
Funding source category [6] 304856 0
Charities/Societies/Foundations
Name [6] 304856 0
The New Zealand Psychological Society
Address [6] 304856 0
PO Box 10536
The Terrace
Wellington 6143
Country [6] 304856 0
New Zealand
Primary sponsor type
Individual
Name
Professor Julia Rucklidge
Address
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country
New Zealand
Secondary sponsor category [1] 296794 0
Individual
Name [1] 296794 0
Associate Professor Caroline Bell
Address [1] 296794 0
Department of Psychological Medicine
University of Otago
PO Box 4345
Christchurch 8140
Country [1] 296794 0
New Zealand
Other collaborator category [1] 279782 0
Individual
Name [1] 279782 0
Claire Gilbert
Address [1] 279782 0
Anxiety Disorders Service
Canterbury District Health Board
Private Bag 4733
Christchurch 8140
Country [1] 279782 0
New Zealand
Other collaborator category [2] 279783 0
Individual
Name [2] 279783 0
Associate Professor Joseph Boden
Address [2] 279783 0
University of Otago
Terrace House
Level 2/4 Oxford Terrace
Christchurch 8011
Country [2] 279783 0
New Zealand
Other collaborator category [3] 279784 0
Individual
Name [3] 279784 0
Dr Rebecca Nicholls
Address [3] 279784 0
Cashmere Health
4 Colombo Street
Cashmere
Christchurch 8022
Country [3] 279784 0
New Zealand
Other collaborator category [4] 279785 0
Individual
Name [4] 279785 0
Meredith Blampied
Address [4] 279785 0
Department of Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country [4] 279785 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298820 0
Health and Disability Ethics Committee
Ethics committee address [1] 298820 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 298820 0
New Zealand
Date submitted for ethics approval [1] 298820 0
25/07/2017
Approval date [1] 298820 0
14/11/2017
Ethics approval number [1] 298820 0
17/STH/131

Summary
Brief summary
Anxiety and depression in adults are highly prevalent and impairing health conditions in New Zealand. The cost to the New Zealand health system and society in treating these difficulties is great. Current best evidence treatment for mental health issues includes medication and psychotherapy. Whilst fairly accessible via prescriptions, medication
for mental health can have a range of side effects such as weight gain, agitation and loss of libido. Although avoiding these side effects, psychotherapy can be difficult to access in the community due to cost and limited resources. In addition, both psychotropic medication and psychotherapy do not work for all individuals experiencing anxiety and depression. Research has indicated that micronutrients (vitamins and minerals) play an important role
in mental health and that administration of micronutrients over and above what can be ingested by diet alone can assist in improving mood liability, improve concentration, stress, general anxiety, and low mood. Research using micronutrients as a treatment for mental health issues has provided a reassuring safety profile. There have been few well controlled
trials investigating the effect of micronutrients specifically on anxiety and depression in adults, in particular in the community. This trial aims to randomly assign participants to receive either micronutrients or placebo and measure the impact micronutrients have on anxiety and depression.
Trial website
Trial related presentations / publications
Public notes
Hardy Nutritionals (Registered Trademark) are the manufacturer of the study intervention and placebo and have no other involvement in the study other than donating the product free of charge.

Contacts
Principal investigator
Name 78334 0
Ms Meredith Blampied
Address 78334 0
Mental Health and Nutrition Research Group
Department of Psychology
University of Canterbury
Private Bag 4800,
Christchurch 8140
Country 78334 0
New Zealand
Phone 78334 0
+64 3 369 2836
Fax 78334 0
+64 33642181
Email 78334 0
mindmappsychology@gmail.com
Contact person for public queries
Name 78335 0
Ms Meredith Blampied
Address 78335 0
Mental Health and Nutrition Research Group
Department of Psychology
University of Canterbury
Private Bag 4800,
Christchurch 8140
Country 78335 0
New Zealand
Phone 78335 0
+64 22 153 3702
Fax 78335 0
+64 33642181
Email 78335 0
mindmappsychology@gmail.com
Contact person for scientific queries
Name 78336 0
Prof Julia Rucklidge
Address 78336 0
Mental Health and Nutrition Research Group
Department of Psychology
University of Canterbury
Private Bag 4800,
Christchurch 8140
Country 78336 0
New Zealand
Phone 78336 0
+64 3369 4398
Fax 78336 0
+64 33642181
Email 78336 0
julia.rucklidge@canterbury.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
Participants in this trial have not consented to their data being shared in such a way.
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 1255 0
Study protocol
Citation [1] 1255 0
Link [1] 1255 0
Email [1] 1255 0
Other [1] 1255 0
Summary results
No Results