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Trial registered on ANZCTR


Registration number
ACTRN12613000896774
Ethics application status
Approved
Date submitted
18/07/2013
Date registered
12/08/2013
Date last updated
30/01/2019
Date data sharing statement initially provided
30/01/2019
Date results information initially provided
30/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized controlled trial investigating the efficacy and safety of a micronutrient formula in the treatment of Attention-Deficit/Hyperactivity Disorder in children
Scientific title
Investigation into the effect of a nutritional supplement on ADHD symptoms in a clinical sample of children with Attention-Deficit/Hyperactivity Disorder (ADHD): a double blind randomized placebo controlled trial with open label extension.
Secondary ID [1] 282817 0
none
Universal Trial Number (UTN)
U1111-1139-8257
Trial acronym
REST-M for ADHD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
ADHD 289599 0
Condition category
Condition code
Alternative and Complementary Medicine 289935 289935 0 0
Other alternative and complementary medicine
Mental Health 290049 290049 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Double blind randomized controlled trial (RCT) comparing a mineral and vitamin supplement (Daily Essential Nutrients) with a placebo followed with an open-label extension. The intervention consists of a micronutrient formula (Daily Essential Nutrients) containing 41 ingredients: The doses of each ingredient of one capsule are:
Vitamin A (as retinyl palmitate) 384 IU
Vitamin C (as ascorbic acid) 40 mg
Vitamin D (as cholecalciferol) 200 IU
Vitamin E (as d-alpha tocopheryl succinate) 24 IU
Vitamin K (as phylloquinone) 6 mcg
Vitamin K (as menaquinone-7) 2 mcg
Thiamin (as thiamin mononitrate) 4 mg
Riboflavin 1.2 mg
Niacin (as niacinamide) 6 mg
Vitamin B6 (as pyridoxine hydrochloride) 4.6667 mg
Folate (as folic acid) 50 mcg
Folate (as L-methylfolate calcium) 50 mcg
Vitamin B12 (as methylcobalamin) 60 mcg
Biotin 72 mcg
Pantothenic acid (as d-calcium pantothenate) 2 mg
Calcium (as chelate) 88 mg
Iron (as chelate) 0.916 mg
Phosphorus (as chelate) 56 mg
Iodine (as chelate) 13.6 mcg
Magnesium (as chelate) 40 mg
Zinc (as chelate) 3.2 mg
Selenium (as chelate) 13.6 mcg
Copper (as chelate) 0.48 mg
Manganese (as chelate) 0.64 mg
Chromium (as chelate) 41.6 mcg
Molybdenum (as chelate) 9.6 mcg
Potassium (as chelate) 16 mg

Proprietary blend: Choline bitartrate, Alpha-lipoic acid, Inositol, Acetylcarnitine (as acetyl-L-carnitine hydrochloride), Grape seed extract, Ginkgo biloba leaf extract,, Methionine (as L-methionine hydrochloride), Cysteine (as N-acetyl-L-cysteine), Germanium sesquioxide (as chelate), Boron, Vanadium, Lithium orotate, Nickel.

Other ingredients:
Cellulose 49.122 mg
Glycine 45 mg
Citric acid 26.814 mg
Magnesium stearate 24 mg
Silicon dioxide 20 mg

Participants swallow up to a target dose of 12 capsules a day divided into three doses of 4 pills each dose for a total of 10 weeks. Participants will begin by taking one capsule, 3 times each day, increasing the dose by three capsules every two days up to a target dose of 12 capsules per day: 4 taken at 3 different intervals (or the equivalent in powder form). Some participants may need to increase the dose more slowly. They then enter an open label trial for a further 10 weeks with the same dose of Daily Essential Nutrients (DEN). Compliance will be monitored with diaries and pill counts. All participants will then be followed up naturalistically 6 months and 1 year post trial.
Intervention code [1] 287502 0
Treatment: Other
Comparator / control treatment
Placebo: The placebo consists of riboflavin, fiber acacia gum, Maltodextrin, and cocoa powder. Patients swallow 12 capsules a day divided into three doses of 4 pills each dose for a total of 10 weeks. They then enter an open label trial for a further 10 weeks with the same dose of DEN (ingredients described above).
Control group
Placebo

Outcomes
Primary outcome [1] 289988 0
ADHD Rating Scale -IV (clinician)
Timepoint [1] 289988 0
baseline, 10 weeks (end of RCT), 20 weeks (end of open-label), 6 and 12 months post-trial
Primary outcome [2] 289989 0
Clinician Clinical Global Impression (CGI)
Timepoint [2] 289989 0
every two weeks during the trial, 10 weeks (end of RCT), every two weeks during the open label phase, 20 weeks (end of open-label), 6 and 12 months post-trial. Data collected bimonthly (ie between asssessment phases) will only be used if there is a dropout or a withdrawal.
Primary outcome [3] 292296 0
Conners Parent Rating Scale Long Version (CPRS-R:L) - the DSM-IV Inattentive, DSM-IV Hyperactive-Impulsive and DSM-IV:Total subscales.
Timepoint [3] 292296 0
baseline, 10 weeks (end of RCT), 20 weeks (end of open-label), 6 and 12 months post-trial.
At bimonthly intervals the ADHD Rating Scale IV will be administered and only used in the case of dropouts or withdrawals from the study. The ADHD Rating Scale IV contains the exact same items as the DSM-IV Inattentive and DSM-IV Hyperactive-Impulsive subscales of the CPRS-R:L.
Secondary outcome [1] 303721 0
vitamin and mineral analysis using serum and hair analysis
Timepoint [1] 303721 0
baseline, 10 weeks (end of RCT) for serum
baseline, 6 months post trial for hair
Secondary outcome [2] 303722 0
fMRI for a subset of 20 participants; First, high resolution anatomical MRI will be collected. Short echo (TE = 30 msec, TR = 2000 msec) 1H-MRS protocol will consist of two striatal voxels (right and left, 4cc, 192 averages) and two prefrontal voxels (4cc, 128 averages). All voxels will be analyzed using LCModel. Metabolites include glutamate and creatine. While the child is in the scanner, we will also conduct Diffusion Tensor Imaging (DTI): sensitive to tissue microstructure; Arterial Spin Labelling (ASL): provides non-invasive, whole-brain, quantitative cerebral perfusion measures and resting state functional connectivity: This is an fMRI acquisition with no task (actually the task is to stare at a cross). This allows inference of functional connectivity. We will also include at least 2 more clinically useful scans: a T2 and T2 FLAIR scan to help with a radiological screening.
Timepoint [2] 303722 0
baseline, 10 weeks (end of RCT)
Secondary outcome [3] 303723 0
Strengths and Difficulties Questionnaire
Timepoint [3] 303723 0
baseline, 10 weeks (end of RCT), 20 weeks (end of open-label), 6 and 12 months post-trial
Secondary outcome [4] 303724 0
The Behavior Rating Inventory of Executive Function
Timepoint [4] 303724 0
baseline, 10 weeks (end of RCT), 20 weeks (end of open-label)
Secondary outcome [5] 303725 0
Child Mania Rating Scale, Parent Version
Timepoint [5] 303725 0
baseline, every two weeks during the blind trial, 10 weeks (end of RCT), every two weeks during the open label phase, 20 weeks (end of open-label), 6 and 12 months post-trial
Secondary outcome [6] 303726 0
Children’s Global Assessment Scale
Timepoint [6] 303726 0
baseline, every two weeks during the blind trial, 10 weeks (end of RCT), every two weeks during the open label phase, 20 weeks (end of open-label), 6 and 12 months post-trial
Secondary outcome [7] 303809 0
Screen for Child Anxiety Related Disorders-Revised
Timepoint [7] 303809 0
baseline, 10 weeks (end of RCT), 20 weeks (end of open-label), 6 and 12 months post-trial
Secondary outcome [8] 304127 0
Conners Teacher Rating Scale - Revised (CTRS-R)
Timepoint [8] 304127 0
baseline, 10 weeks (end of RCT)
Secondary outcome [9] 304128 0
Child Depression Rating Scale
Timepoint [9] 304128 0
baseline, every two weeks during the blind trial, 10 weeks (end of RCT), every two weeks during the open label phase, 20 weeks (end of open-label), 6 and 12 months post-trial
Secondary outcome [10] 304129 0
neurocognitive assessment (working memory, processing speed, cognitive flexibility)
Timepoint [10] 304129 0
baseline, 10 weeks (end of RCT)
Secondary outcome [11] 308675 0
Social Skills Improvement System (SSIS) Rating Scales
Timepoint [11] 308675 0
baseline, 10 weeks (end of RCT), 20 weeks (end of open-label)
Secondary outcome [12] 322181 0
microbiome via fecal sampling
Timepoint [12] 322181 0
baseline and end of RCT

Eligibility
Key inclusion criteria
1) between 7 and 12 years, 2) considered reliable and compliant with the protocol (including the ingestion of as many as 12 capsules/day with food), and 3) meet criteria for ADHD as assessed by the K-SADS, and the Conners Rating Scales (T score greater than 65 on both parent and teacher form for any of the ADHD DSM-IV subscales).
A subset (n=20) of children (males with Combined ADHD) will be asked to participate in an 1H-MRS pilot study in order to begin documenting the impact that nutrition has on the brains of ADHD children. Those participants must be compatible with the imaging scanner (i.e. no braces, no history of claustrophobia).
Minimum age
7 Years
Maximum age
12 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Neurological disorder involving brain or other central function (e.g., intellectual disability as assessed by the Wechsler Intelligence Scale for Children, autism spectrum disorder, epilepsy, MS, narcolepsy) or other major psychiatric condition requiring hospitalization (e.g. significant mood disorder or psychosis), 2) Any serious medical condition, 3) Any patient known to be allergic to the ingredients of the intervention, 4) Any known abnormality of mineral metabolism (e.g., Wilson’s disease, haemochromatosis), 5) Any other medication with primarily central nervous system activity, including stimulants. Participants must have been off of these medications for a minimum of four weeks prior to the trial.

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)
Provided that an individual meets the inclusion criteria and does not meet exclusion criteria, the person is allocated the next available number. All pills (ie active ingredient or placebo) have been pre-packaged by the pharmacy who holds the randomization code. A sealed envelope is contained within each pill package only to be opened in an emergency (ie patient deteriorates significantly).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization will be done using software produced by www.randomization.com. Four lists will be generated and the pharmacy will randomly chose one list to use for the randomization.
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
The randomized phase is followed with an open-label trial
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Based on our initial pilot results (most effect sizes estimated at .8-1.2), using power = .8 to detect a large effect size (.8), with a two-tailed a=0.05, we estimate needing about 35 participants per group, a number we should be able to recruit over a two year period given our proven success in recruitment for the open-label ABAB trial. Assuming a 10-15% dropout and to allow for multiple analyses, we will aim for 50 per group.
The changes from baseline to the end of treatment will be compared between randomized groups using repeated-measures ANCOVA, with the baseline level as the covariate. Change measures assessed at the end of treatment with no baseline will be compared using one-way ANOVA. The differences between treatment groups in these measures will be summarized as the mean differences and 95% confidence intervals generated from the ANCOVA/ANOVA models. Categorical outcomes will be compared between groups using Chi-square tests and will be described using odds ratios and 95% confidence intervals. All analyses will be undertaken on an intention-to-treat (ITT) basis that includes all randomized participants analyzed according to the group to which they were randomized. For those participants not completing the 10 weeks, data from their final assessment will be used to evaluate the change scores. Secondary analyses will be undertaken on all outcomes using the per-protocol (completers) analysis set. All tests will be two tailed and any p values less than 0.05 will be considered statistically significant.

Recruitment
Recruitment status
Completed
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] 5188 0
New Zealand
State/province [1] 5188 0
Canterbury

Funding & Sponsors
Funding source category [1] 287600 0
University
Name [1] 287600 0
University of Canterbury
Address [1] 287600 0
Department of Psychology
University of Canterbury
Private Bag 4800
Ilam 8140
Christchurch
Country [1] 287600 0
New Zealand
Primary sponsor type
University
Name
University of Canterbury
Address
Department of Psychology
University of Canterbury
Private Bag 4800
Ilam 8140
Christchurch
Country
New Zealand
Secondary sponsor category [1] 286376 0
University
Name [1] 286376 0
University of Calgary
Address [1] 286376 0
Behavioural Research Unit, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8

Country [1] 286376 0
Canada

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289575 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 289575 0
1 the Terrace
PO Box 5013
Wellington
6011
Ethics committee country [1] 289575 0
New Zealand
Date submitted for ethics approval [1] 289575 0
Approval date [1] 289575 0
28/05/2013
Ethics approval number [1] 289575 0
13/STH/45
Ethics committee name [2] 289719 0
Human Ethics Committee
Ethics committee address [2] 289719 0
University of Canterbury
Private Bag 4800
Christchurch
Ethics committee country [2] 289719 0
New Zealand
Date submitted for ethics approval [2] 289719 0
Approval date [2] 289719 0
09/08/2013
Ethics approval number [2] 289719 0
HEC 2013/28/LR-PS

Summary
Brief summary
Attention Deficit/Hyperactivity Disorder (ADHD) is a chronic, debilitating psychiatric illness which begins in childhood, affecting 3-7% of the population worldwide. It is associated with many other psychiatric conditions and serves as a risk factor for offending behaviour and continued mental health problems into adulthood. While many treatments are widely used for ADHD, the side effects and lack of long-term efficacy data cause many families to seek out alternatives. Despite the growing popularity of complementary alternative medicines (CAM), there is very little research into the impact of CAM on psychiatric illness. This study aims to investigate the impact of micronutrients on children with ADHD. One micronutrient formula called Daily Essential Nutrients (DEN), a revision of EMPowerplus(EMP+) which is sold in NZ, has received international attention as a treatment for several
psychiatric disorders including bipolar disorder, depression and ADHD. Our research team has published results using a variety of designs including open label, case studies and RCTs, showing that EMP+ has significant positive effects on mood, anxiety, hyperactivity, impulsivity and emotional lability. Given the encouraging results to date, this study seeks to conduct a randomized controlled trial of EMP+ using this revised formula, DEN, for children 7-12 years of age.
Trial website
www.mentalhealthandnutrition.co.nz
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 41382 0
Prof Julia Rucklidge
Address 41382 0
Department of Psychology University of Canterbury Private Bag 4800 Christchurch 8140 New Zealand
Country 41382 0
New Zealand
Phone 41382 0
+64 3 3642987 ext7959
Fax 41382 0
Email 41382 0
julia.rucklidge@canterbury.ac.nz
Contact person for public queries
Name 41383 0
Prof Julia Rucklidge
Address 41383 0
Department of Psychology University of Canterbury Private Bag 4800 Christchurch 8140 New Zealand
Country 41383 0
New Zealand
Phone 41383 0
+64 3 3642987 ext7959
Fax 41383 0
Email 41383 0
julia.rucklidge@canterbury.ac.nz
Contact person for scientific queries
Name 41384 0
Prof Julia Rucklidge
Address 41384 0
Department of Psychology University of Canterbury Private Bag 4800 Christchurch 8140 New Zealand
Country 41384 0
New Zealand
Phone 41384 0
+64 3 3642987 ext7959
Fax 41384 0
Email 41384 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
The participants did not give consent to data sharing
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 1220 0
Rucklidge, J. J., Eggleston, M., Johnstone, J. M., Darling, K., & Frampton, C. M. (2018). Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: A fully-blinded, randomized, placebo-controlled trial. Journal of Child Psychology and Psychiatry, 59(3), 232-246. http://onlinelibrary.wiley.com/doi/10.1111/jcpp.12817/full

Attachments [1] 1220 0
Publication date and citation/details [2] 1241 0
Stevens, A., Rucklidge, J. J., Eggleston, M., Darling, K., & Kennedy, M. (2018). Methylomic changes in response to micronutrient supplementation and MTHFR genotype. Epigenomics, 10(8), 1201-1214. https://www.futuremedicine.com/doi/10.2217/epi-2018-0029
Attachments [2] 1241 0
Publication date and citation/details [3] 1242 0
Rucklidge, J. J., Eggleston, M., Johnstone, J. M., Darling, K., Stevens, A. J., Kennedy, M. A., & Frampton, C. M. (2019). Can we predict treatment response in children with ADHD to a vitamin-mineral supplement? An investigation into pre-treatment nutrient serum levels, MTHFR status, clinical correlates and demographic variables. Progress in Neuropsychopharmacology & Biological Psychiatry, 89, 181-192. https://www.sciencedirect.com/science/article/pii/S027858461830407X?via%3Dihub
Attachments [3] 1242 0
Publication date and citation/details [4] 1243 0
Borlase, N., Melzer, T. R., Eggleston, M., Darling, K., & Rucklidge, J. J. (2019). Resting-state networks and neurometabolites in children with ADHD after 10 weeks of treatment with micronutrients: results of a randomised placebo-controlled trial. Accepted Nutritional Neuroscience.
Attachments [4] 1243 0
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary