ANZCTR - Registration

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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]

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

Condition category

Condition code

Alternative and Complementary Medicine

Other alternative and complementary medicine

Mental Health

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]

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]

ADHD Rating Scale -IV (clinician)

Timepoint [1]

baseline, 10 weeks (end of RCT), 20 weeks (end of open-label), 6 and 12 months post-trial

Primary outcome [2]

Clinician Clinical Global Impression (CGI)

Timepoint [2]

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]

Conners Parent Rating Scale Long Version (CPRS-R:L) - the DSM-IV Inattentive, DSM-IV Hyperactive-Impulsive and DSM-IV:Total subscales.

Timepoint [3]

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]

vitamin and mineral analysis using serum and hair analysis

Timepoint [1]

baseline, 10 weeks (end of RCT) for serum
baseline, 6 months post trial for hair

Secondary outcome [2]

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]

baseline, 10 weeks (end of RCT)

Secondary outcome [3]

Strengths and Difficulties Questionnaire

Timepoint [3]

baseline, 10 weeks (end of RCT), 20 weeks (end of open-label), 6 and 12 months post-trial

Secondary outcome [4]

The Behavior Rating Inventory of Executive Function

Timepoint [4]

baseline, 10 weeks (end of RCT), 20 weeks (end of open-label)

Secondary outcome [5]

Child Mania Rating Scale, Parent Version

Timepoint [5]

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]

Children’s Global Assessment Scale

Timepoint [6]

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]

Screen for Child Anxiety Related Disorders-Revised

Timepoint [7]

baseline, 10 weeks (end of RCT), 20 weeks (end of open-label), 6 and 12 months post-trial

Secondary outcome [8]

Conners Teacher Rating Scale - Revised (CTRS-R)

Timepoint [8]

baseline, 10 weeks (end of RCT)

Secondary outcome [9]

Child Depression Rating Scale

Timepoint [9]

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]

neurocognitive assessment (working memory, processing speed, cognitive flexibility)

Timepoint [10]

baseline, 10 weeks (end of RCT)

Secondary outcome [11]

Social Skills Improvement System (SSIS) Rating Scales

Timepoint [11]

baseline, 10 weeks (end of RCT), 20 weeks (end of open-label)

Secondary outcome [12]

microbiome via fecal sampling

Timepoint [12]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/09/2013

Actual

10/09/2013

Date of last participant enrolment

Anticipated

1/11/2016

Actual

7/10/2016

Date of last data collection

Anticipated

31/10/2017

Actual

1/01/2018

Sample size

Target

100

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Canterbury

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Canterbury

Address [1]

Department of Psychology
University of Canterbury
Private Bag 4800
Ilam 8140
Christchurch

Country [1]

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]

University

Name [1]

University of Calgary

Address [1]

Behavioural Research Unit, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8

Country [1]

Canada

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Southern Health and Disability Ethics Committee

Ethics committee address [1]

1 the Terrace
PO Box 5013
Wellington
6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

Approval date [1]

28/05/2013

Ethics approval number [1]

13/STH/45

Ethics committee name [2]

Human Ethics Committee

Ethics committee address [2]

University of Canterbury
Private Bag 4800
Christchurch

Ethics committee country [2]

New Zealand

Date submitted for ethics approval [2]

Approval date [2]

09/08/2013

Ethics approval number [2]

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

Prof Julia Rucklidge

Address

Department of Psychology University of Canterbury Private Bag 4800 Christchurch 8140 New Zealand

Country

New Zealand

Phone

+64 3 3642987 ext7959

Fax

[email protected]

Contact person for public queries

Name

Prof Julia Rucklidge

Address

Department of Psychology University of Canterbury Private Bag 4800 Christchurch 8140 New Zealand

Country

New Zealand

Phone

+64 3 3642987 ext7959

Fax

[email protected]

Contact person for scientific queries

Name

Prof Julia Rucklidge

Address

Department of Psychology University of Canterbury Private Bag 4800 Christchurch 8140 New Zealand

Country

New Zealand

Phone

+64 3 3642987 ext7959

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

The participants did not give consent to data sharing

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	Citations or Other Details
Study results article	Yes	Rucklidge, J. J., Eggleston, M., Johnstone, J. M.,... [More Details]
Study results article	Yes	Stevens, A., Rucklidge, J. J., Eggleston, M., Darl... [More Details]
Study results article	Yes	Rucklidge, J. J., Eggleston, M., Johnstone, J. M.,... [More Details]
Study results article	Yes	Borlase, N., Melzer, T. R., Eggleston, M., Darling... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	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.	2019	https://dx.doi.org/10.1016/j.pnpbp.2018.09.007
Embase	Resting-state networks and neurometabolites in children with ADHD after 10 weeks of treatment with micronutrients: results of a randomised placebo-controlled trial.	2020	https://dx.doi.org/10.1080/1028415X.2019.1574329
Embase	Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial.	2018	https://dx.doi.org/10.1111/jcpp.12817

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically