Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000399897
Ethics application status
Approved
Date submitted
8/02/2021
Date registered
9/04/2021
Date last updated
1/12/2023
Date data sharing statement initially provided
9/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The Taiora Trial: A community-based randomized placebo-controlled trial evaluating micronutrients for emotion dysregulation in teenagers experiencing mood problems
Scientific title
The efficacy of micronutrients as a treatment for emotional dysregulation in teenagers experiencing mood difficulties/problems: A community randomized placebo-controlled trial
Secondary ID [1] 303321 0
NIL
Universal Trial Number (UTN)
U1111-1253-6457
Trial acronym
BEAM: Balancing Emotions for Adolescents with Micronutrients
Linked study record
n/a

Health condition
Health condition(s) or problem(s) studied:
Emotion dysregulation 320553 0
Condition category
Condition code
Mental Health 318410 318410 0 0
Other mental health disorders

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 eight weeks. After eight weeks, all participants will enter into an open-label phase whereby all participants can choose to take the micronutrient formula for another eight 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), 1,728mcg; Vitamin C (as ascorbic acid), 600 mg; Vitamin D (as cholecalciferol), 72mcg; Vitamin E (as d-alpha tocopheryl succinate), 194.4mg; Vitamin K (75% as phylloquinone; 25% as menaquinone-7), 120 mcg; Thiamin (as thiamin HCI), 60 mg; Riboflavin, 18 mg; Niacin (as niacinamide, nicotinamide riboside CI, & nicotinic acid), 144 mg; Vitamin B6 (as pyridoxine HCI & pyridoxal-5-hosphate), 60 mg; Folate (as calcium folinate & L-methylfolate calcium), 1,500 mcg DFE; Vitamin B12 (as hydroxo-, adenosyl-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 (from Atlantic kelp), 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: Alpha-lipoic acid, Great Salt Lake minerals, Inositol, Acetyl-L-carnitine HCI, Atlantic kelp (laminaria digitata), grape seed extract, Ginkgo biloba leaf extract, L-methionine, N-acetyl-L-cysteine, mixed tocopherols (organic), mixed tocotrienols (from palm fruit), trace minerals as NutraTek chelation complex, Boron, Vanadium, 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 weekly period and photograph unused or missed capsules, submitting photos to the study website.
Intervention code [1] 319628 0
Treatment: Other
Comparator / control treatment
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:
Yellow corn masa flour 6652mg
White rice flour 543mg
Caramel color powder 242mg
Magnesium stearate 51mg
Microcrystalline cellulose 51mg
Silicon Dioxide 19mg
Riboflavin 1.2mg
Hypromellose capsule 1632mg
(contains HPMC & titanium dioxide)

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.

All participants will report on missed doses each week as part of weekly monitoring and will provide a photo of leftover pills at the end of the RCT.
Control group
Placebo

Outcomes
Primary outcome [1] 326423 0
Clinical Global Impression - Improvement (CGI-I)
Timepoint [1] 326423 0
4 weeks RCT, End of RCT (Week 8), 4 weeks into open-label (week 12), end of open label (week 16), 1 year follow up (week 52). End of RCT (week 8) is considered the primary endpoint although the data will be analyzed with linear mixed modelling over time.
Primary outcome [2] 326424 0
The Emotion Dysregulation Inventory (EDI)
Timepoint [2] 326424 0
Baseline (week 0), weekly during RCT (week 1 through 8), end of RCT (Week 8), weekly in open label (week 9 through week 15), end of open label (week 16), 1 year follow up (week 52). End of RCT (week 8) is considered the primary endpoint. However, the data will be analyzed using linear mixed modelling to assess for the effect of time on the primary outcome measure.
Primary outcome [3] 326425 0
Clinician-rated Temper and Irritability Scale (CL-ARI)
Timepoint [3] 326425 0
4 weeks RCT, End of RCT (Week 8), 4 weeks into open-label (week 12), end of open label (week 16), 1 year follow up (week 52). End of RCT (week 8) is considered the primary endpoint although the data will be analyzed with linear mixed modelling over time.
Secondary outcome [1] 391423 0
The Affective Reactivity Index (ARI)
Timepoint [1] 391423 0
Baseline (week 0), weekly during RCT (week 1 through 8), end of RCT (Week 8), weekly in open label (week 9 through week 15), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [2] 391424 0
The Kessler psychological distress scale (K10)
Timepoint [2] 391424 0
Baseline (week 0), end of RCT (Week 8), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [3] 391425 0
Generalised Anxiety Disorder 7-Question Scale (GAD-7)
Timepoint [3] 391425 0
Baseline (week 0), weekly during RCT (week 1 through 8), end of RCT (Week 8), weekly in open label (week 9 through week 15), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [4] 391426 0
Brief Resilience Scale (BRS)
Timepoint [4] 391426 0
Baseline (week 0), end of RCT (Week 8), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [5] 391427 0
Modified Participant/Parent Global Impression (PGI-I)
Timepoint [5] 391427 0
weekly during RCT (week 1 through 8), end of RCT (Week 8), weekly in open label (week 9 through week 15), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [6] 391428 0
Strengths and Difficulties Questionnaires (Parent form). This is a composite measure that parents fill out assessing their child's strengths and difficulties.
Timepoint [6] 391428 0
Baseline (week 0), end of RCT (Week 8), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [7] 391429 0
The paediatric quality of life enjoyment and satisfaction questionnaire (PQ-LES-Q). This is a self-report questionnaire that the child fills out about their quality of life.
Timepoint [7] 391429 0
Baseline (week 0), end of RCT (Week 8), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [8] 391431 0
Children's Revised Impact of Events Scale (CRIES). This will be completed by the clinician.
Timepoint [8] 391431 0
Baseline (week 0), end of RCT (Week 8), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [9] 391432 0
The Perceived Stress Scale (PSS)
Timepoint [9] 391432 0
Baseline (week 0), end of RCT (Week 8), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [10] 391434 0
Parent Target Problem (PTP)
Timepoint [10] 391434 0
Baseline (week 0), 4 weeks RCT, End of RCT (Week 8), 4 weeks into open-label (week 12), end of open label (week 16), 1 year follow up (week 52). End of RCT (week 8) is considered the primary endpoint although the data will be analyzed with linear mixed modelling over time.
Secondary outcome [11] 391435 0
Children's Global Assessment Scale (CGAS)
Timepoint [11] 391435 0
Baseline (week 0), end of RCT (week 8), end of open label (week 16).
Secondary outcome [12] 391436 0
Clinical Global Impression Severity Scale (CGI-I)
Timepoint [12] 391436 0
Baseline (week 0), end of RCT (week 8), end of open label (week 16).
Secondary outcome [13] 391438 0
Dietary Screening Tool (DST)
Timepoint [13] 391438 0
Baseline (week 0), end of RCT (week 8), end of open label (week 16).
Secondary outcome [14] 391440 0
The Side-Effect Checklist (ASEC). This will measure possible adverse physical events experienced during the trial. All side effects will be assessed through self report and any concerning side effects will be referred to our trial physician or their general practitioner. The most common side effects reported in micronutrient trials are nausea, headaches and a dry mouth.
Timepoint [14] 391440 0
Baseline (week 0), weekly during RCT (week 1 through 8), end of RCT (Week 8), weekly in open label (week 9 through week 15), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [15] 392608 0
Strengths and Difficulties Questionnaire (Child Form) This is a composite measure that children fill out assessing their strengths and difficulties.
Timepoint [15] 392608 0
Baseline (week 0), end of RCT (Week 8), end of open label (week 16), 1 year follow up (week 52).
Secondary outcome [16] 392703 0
The Clinician Rated Colombia Impairment Scale
Timepoint [16] 392703 0
Baseline (week 0), end of RCT (Week 8), end of open label (week 16), 1 year follow up (week 52).

Eligibility
Key inclusion criteria
1) between 12 and 17 years, 2) regular access to the internet/phone, 3) living in New Zealand, 4) considered reliable and compliant with protocol (including ingestion of as many as 12 capsules/day with food), 5) be presenting to their GP or school counsellor with functionally impairing emotional dysregulation which cannot be better accounted for by a medical condition or parental identified as showing disabling emotions that are interfering with their ability to function, 6) sufficient ability to read and write English in order to complete questionnaires, 7) be attending primary or high school, and 8) receive a CGI-S rating of at least 4 (moderately ill) on screening and a minimum score of 10 on the Emotion Dysregulation Inventory or 3 on the Affective Reactivity Index.
Minimum age
12 Years
Maximum age
17 Years
Sex
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) Known neurological disorders involving brain or other central function (e.g., previously diagnosed 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) pregnant or breastfeeding, and 4) Any medications with primarily central nervous system activity, including psychotropic medication (e.g. SSRIs, tricyclics, benzodiazepines). Participants must have been off these medications for a minimum of four weeks prior to the trial. Participants will not be encouraged to come off a medication in order to participate.

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 the trial statistician and will be arranged in a 1:1 ratio using blocks and stratified by gender.
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
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Based on previous studies that examined the treatment of emotional dysregulation using broad-spectrum micronutrients compared with placebo in children with ADHD (d=0.66), an effect size of d=0.5 was chosen. As such, the total number of participants required would be 126 (63 in each group). Attrition rates in these types of studies can range between 3-19%. Allowing for a 20% attrition rate, the adjusted number-per-treatment condition would be 75 and total sample size required would be 150 randomized 1:1 to the two conditions.

All data will be analysed on an intent-to-treat and per-protocol populations. All measures will be analysed using generalised linear mixed-effect regression models and effect sizes will be reported using Cohen’s d. Clinically significant outcomes will be determined by calculating the Reliable Change Index.
The intention to treat (ITT) population for the primary analyses of outcomes will include all randomised participants. For the ITT population, if there is no exit effectiveness evaluation then the last evaluation will be carried forward, this may be the baseline assessment in some circumstances. This is also how missing data will be handled. For the ITT analyses, participants are analysed according to their randomly allocated treatment group irrespective of the actual treatment received.
The safety population, which will be used for all safety analyses, will include all participants who have taken at least one dose of study product. Treatment groups will be defined as the actual treatment received irrespective of randomised treatment.
The per-protocol (PP) population for each efficacy measure will include all participants who take at least 75% of the allocated pills, have no significant protocol deviations and have all appropriate assessments relevant to the outcome.

The observation period for the efficacy endpoints from the double-blind phase will be from the baseline (pre-intervention) up to the 8 week assessment. The observation period for the efficacy endpoints from the open-label extension will be from the 8 week (end of double blind phase) up to the 16 week assessment, end of open label phase.

Demographic characteristics will be compared across the treatment groups using independent samples t-tests in order to test for potential failures of randomization. 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, 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 covariate factors, as well as measures of demographic characteristics. 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). The CGI-I will also be reported as responder/non-responder by group using chi-square analyses/odds ratios. A score of 1 or 2 (very much improved and much improved) will be used to identify responders.

For secondary outcomes, 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. For secondary outcomes, linear mixed effects models will also be used, to explore the relationship between other psychiatric difficulties and the micronutrient intervention. Covariates will also be included that have been shown to affect outcomes including, but not limited to, personality, gender, socio-economic status, past psychiatric medication use.

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.

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.
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.

It is intended that all statistical analyses specified in this protocol will be performed. However, it is conceivable that some scheduled analyses may not be performed. In addition, study observations or analysis results may suggest the need for additional statistical analyses of the collected study data. In either case, deviations (subtractions or additions) from the planned statistical analysis will be fully described in the final study report.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/05/2021
Actual
1/10/2021
Date of last participant enrolment
Anticipated
1/06/2024
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
150
Accrual to date
114
Final
Recruitment outside Australia
Country [1] 23432 0
New Zealand
State/province [1] 23432 0
All

Funding & Sponsors
Funding source category [1] 307737 0
Government body
Name [1] 307737 0
Health Research Council
Country [1] 307737 0
New Zealand
Funding source category [2] 307772 0
Commercial sector/Industry
Name [2] 307772 0
Hardy Nutritionals (Registered Trademark)
Country [2] 307772 0
Canada
Primary sponsor type
Individual
Name
Professor Julia Rucklidge
Address
School of Psychology, Speech and Hearing
University of Canterbury
Private Bag 4800
Christchurch 8140
Country
New Zealand
Secondary sponsor category [1] 308474 0
Individual
Name [1] 308474 0
Ms Meredith Blampied
Address [1] 308474 0
School of Psychology, Speech and Hearing
University of Canterbury
Private Bag 4800
Christchurch 8140
Country [1] 308474 0
New Zealand
Secondary sponsor category [2] 308475 0
Individual
Name [2] 308475 0
Ms Leona Manna
Address [2] 308475 0
School of Psychology, Speech and Hearing
University of Canterbury
Private Bag 4800
Christchurch 8140
Country [2] 308475 0
New Zealand
Secondary sponsor category [3] 308476 0
Individual
Name [3] 308476 0
Dr Sue Bagshaw
Address [3] 308476 0
Canterbury Charity Hospital
Canterbury Charity Hospital Trust
PO Box 20409
Christchurch 8543
Country [3] 308476 0
New Zealand
Secondary sponsor category [4] 308477 0
Individual
Name [4] 308477 0
Professor Roger Mulder
Address [4] 308477 0
Department of Psychological Medicine
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
New Zealand
Country [4] 308477 0
New Zealand
Secondary sponsor category [5] 308479 0
Individual
Name [5] 308479 0
Professor Joseph Boden
Address [5] 308479 0
Department of Psychological Medicine
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
New Zealand
Country [5] 308479 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307764 0
Health and Disability Ethics Committee
Ethics committee address [1] 307764 0
Ethics committee country [1] 307764 0
New Zealand
Date submitted for ethics approval [1] 307764 0
02/10/2020
Approval date [1] 307764 0
10/12/2020
Ethics approval number [1] 307764 0
20/STH/164

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

Contacts
Principal investigator
Name 108410 0
Prof Julia Rucklidge
Address 108410 0
School of Psychology, Speech and Hearing
University of Canterbury
Private Bag 4800
Christchurch 8140
Country 108410 0
New Zealand
Phone 108410 0
+64 03 3694398
Fax 108410 0
Email 108410 0
julia.rucklidge@canterbury.ac.nz
Contact person for public queries
Name 108411 0
Julia Rucklidge
Address 108411 0
School of Psychology, Speech and Hearing
University of Canterbury
Private Bag 4800
Christchurch 8140
Country 108411 0
New Zealand
Phone 108411 0
+64 03 3694398
Fax 108411 0
Email 108411 0
julia.rucklidge@canterbury.ac.nz
Contact person for scientific queries
Name 108412 0
Julia Rucklidge
Address 108412 0
School of Psychology, Speech and Hearing
University of Canterbury
Private Bag 4800
Christchurch 8140
Country 108412 0
New Zealand
Phone 108412 0
+64 03 3694398
Fax 108412 0
Email 108412 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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
10447Study protocol    381338-(Uploaded-14-10-2021-09-45-34)-Study-related document.docx



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseProtocol for a randomised placebo-controlled trial investigating the efficacy and safety of a vitamin-mineral formula targeting dysregulated emotions in teenagers: The balancing emotions of adolescents with micronutrients (BEAM) study.2022https://dx.doi.org/10.1016/j.conctc.2022.101027
N.B. These documents automatically identified may not have been verified by the study sponsor.