… · web viewtraumatic brain injury (tbi) is defined by changes in brain functions leading to...

Protocol for micronutrients and traumatic brain injury: a feasibility study NZ

Principal Investigator: Professor Julia Rucklidge

Mental Health and Nutrition Research Group

University of Canterbury

Private Bag 4800,

Christchurch 8140, NZ.

Email: [email protected]

PhoNe: 0064 3 369 4398

ContentsBackground............................................................................................................................................4

Aims and Objectives..........................................................................................................................7

Methodology.........................................................................................................................................9“Micronutrients and TBI in children: a feasibility study;” June 2019; UTN: U1111-1230-3860; SHDEC

19/STH/68 1 | P a g e

mailto:[email protected]

Protocol for micronutrients and traumatic brain injury: a feasibility study NZStudy design......................................................................................................................................9

Assessment Tools........................................................................................................................11

Statistical Analysis...........................................................................................................................14

Anticipated costs.............................................................................................................................14

Resources........................................................................................................................................14

Timetable.........................................................................................................................................14

Ethics...............................................................................................................................................15

Research site...................................................................................................................................17

Investigators....................................................................................................................................17

Risk Management............................................................................................................................18

Data ownership...............................................................................................................................18

Conflicts of interest.........................................................................................................................18

References...........................................................................................................................................19

Appendices..........................................................................................................................................22

Appendix A: Daily Essential Nutrients ingredient list.......................................................................22

Appendix C: Schedule of Events......................................................................................................24

Appendix D: Participant Information Sheet and Consent Form: Case Study....................................25

PARTICIPANT INFORMATION SHEET................................................................................................25

What is the purpose of the study?..................................................................................................26

What will be studied?......................................................................................................................26

How will it be studied?....................................................................................................................26

What will my child’s participation involve?.....................................................................................26

What will happen to the blood samples my child provide?.............................................................28

What are the possible benefits of this study?.................................................................................28

What are the possible risks of this study?.......................................................................................28

Can my child take other medications?.............................................................................................29

What if my child’s symptoms increase or s/he has a reaction to the micronutrients?....................29

Who pays for the study?..................................................................................................................29

What if something goes wrong?......................................................................................................30

What are our rights?........................................................................................................................30

What happens after the study or if we change our minds?.............................................................31

Who do I contact for more information or if I have any concerns?.................................................31

GP contact details...............................................................................................................................34

GP’s name:...........................................................................................................................................34

Surgery name:.....................................................................................................................................34

“Micronutrients and TBI in children: a feasibility study;” June 2019; UTN: U1111-1230-3860; SHDEC 19/STH/68 2 | P a g e

Protocol for micronutrients and traumatic brain injury: a feasibility study NZSurgery address:..................................................................................................................................34

Surgery phone number:.......................................................................................................................34

Next of kin...........................................................................................................................................34

Email address:.....................................................................................................................................34

Declaration by participant:.................................................................................................................35

Declaration by member of research team:........................................................................................35



BackgroundTraumatic Brain Injury (TBI) is defined by changes in brain functions leading to confusion,

variation in levels of consciousness, coma, seizures, acute sensory or motor neurological

deficits, neuropsychological deficits, behaviour changes as a consequence of a blunt or

penetrating force to the head (Bruns and Hauser, 2003). The main causes of TBIs have been

identified as road traffic accidents and falls. TBI is the leading cause of death and long- term

disability in children and young adults worldwide and is referred to as a “silent epidemic”

(World Health Organisation, 2007, Schwarzbold Diaz, Tostes Martins, Ruffino, Amante,

Thais, Quevedos, Hohl, Linhares and Walz, 2008). By 2020, the World Health Organization

expects that road traffic accidents, listed as one of the major causes of TBI in children and

young adults, will move from ninth to third cause of burden of disease and second in

developing countries thus increasing the number of TBIs in this population. Identifying TBI

comes with many complexities. A primary issue is the reporting of this type of incident;

individuals with TBIs, particularly those classified as “mild” do not always show signs of brain

function change. Some of the impact on the brain can be microscopic and is not always

detected even with modern neuroimaging techniques (Gatze- Kopp and Shannon, 2008).

Those are generally classified as “mild” TBIs. The vast majority of TBIs, 70% – 90% (McKinlay,

Grace, Horwood, Fergusson, Ridder and MacFarlane,2007; World Health Organisation,

2007), are classified as “mild” and are often considered to not require treatment. The

microscopic changes to the brain structure accompanying this type of injury are likely later

on in life, to affect the individual’s functioning in a variety of domains. Secondary injuries

will develop over time and will not always be linked to the TBI sustained by the individual,

potentially affecting the approach to the treatment of the newly emerged condition.

Each year, in the USA, an estimated 475,000 children between the ages of 0 and fourteen

are treated as a result of a TBI (Gatzke- Kopp and Shannon, 2008). Immediate outcomes of

TBI can sometimes be difficult to assess especially in the case of “mild” head injuries. This

renders incidence and prevalence rates difficult to establish. Incidence numbers are hugely

variable across countries. Even within countries, those numbers are dependent on hospital

policy and admission. Therefore, most researchers agree that the incidence of TBI around

the world is likely to be grossly underestimated.


Protocol for micronutrients and traumatic brain injury: a feasibility study NZIn New Zealand, a couple of studies were conducted to understand both incidence and

prevalence of this type of injury. McKinlay et al. (2007) estimated incidence of 175 per

100,000 per year for individuals aged between 0 and 25 years, with an overall prevalence of

31.6% to age 25 years using the cohort from the Christchurch Health and Development

Study (N = 1265). A similar study was conducted in 2013 in Waikato using multiple sources

of TBIs occurrence records and found an incidence of 790 cases of TBI per 100,000

individuals per year (Feigin et al., 2013). In this sample, 70% of total TBIs were assigned to

the 0 to 34 age group. Despite differences in methodologies both those analyses suggest

that there is indeed a strong underestimation of TBI occurrence. There is very little research

on the incidence of cumulative TBIs. McKinlay et al. (2007) found that a single TBI doubles

the risk of a future TBI and that once a second such injury occurs the risk of a third is

increased by eight-fold.

The developmental consequences of TBIs can also be difficult to anticipate. Factors such as

which areas of the brain have been affected, the age at the time of injury and the family

environment have all be found to be predictors of recovery.

Depending on the area affected, symptoms can differ. Both the dorsolateral prefrontal

cortex and the orbitofrontal cortex have been found to be vulnerable to TBIs due to their

proximity to the inner surface of the skull and their increased potential to suffer

countercoup contusions (Gatze-Kopp and Shannon, 2008). This leads to cognitive, emotional

and behavioural deficits. Some longitudinal studies looking at those deficits have however

found that during the first-year post TBI some recovery can occur. Yeates, Taylor, Wade,

Drotar, Stancin and Minich (2002) showed that the first year post paediatric TBI is marked

by some cognitive recovery. The study also used results from two others, Jaffe et al. (1995)

and Fay et al. (1994), showing that children with moderate and severed TBIs showed

substantial improvement in the first-year post injury but the rate of recovery slowed after

this time.

As well as cognitive impairments, people with TBI also experience an array of behavioural

issues (e.g., aggression and apathy) and emotional dysregulation (e.g., moodiness and

irritability). Some studies have focused on the outcomes of a childhood TBI in adulthood and

found that individuals reported greater anxiety and depression, greater perceive stress,

lower self- esteem, substance abuse, PTSD, personality disorders and ADHD (McMillan,


Protocol for micronutrients and traumatic brain injury: a feasibility study NZTeasdale and Stewart, 2012; Ashman, Gordon, Cantor and Hibbard, 2006; Schachar, Park

and Dennis, 2015). Those who had experienced a childhood TBI also reported lower

relationship quality as adults (Rogers and McKinlay, 2019). This impact on individual’s ability

to create and maintain healthy social interactions and reduce their ability to enter and

remain in stable employment. McMillan, Teasdale and Stewart (2012) found that the

proportion of individuals unfit for work increased to 35%, against 12% before the injury, one

year after sustaining the injury and stabilised for the remaining years of the study to 36% (at

5 to 7 years and then 12 to 14 years).

When reporting on emotional deficits, most studies identify emotional dysregulation and

affect lability as common outcomes of TBI. Research from Eisenberg, Fabes, Guthrie and

Reiser (2000) and Rhoades, Greenberg and Domitrovich (2009) demonstrate the importance

of emotional regulation, resilience and personality in developing good quality social skills in

the future. Self- control in childhood has also been linked to better health, wealth and

decreased criminal activity as adults (Moffit et al., 2010). In addition, Caspi, Harrington,

Amell Theodore and Moffit (2003) found that behavioural style at age 3 was a good

predictor of personality traits at 26. Children were classified into various temperament type

groups. Those with little emotional control, the “under- controlled type”, grew up to score

higher on stress reaction scales, aggression, were more likely to express negative emotions

in reactions to ordinary circumstances, and had the lowest scored on social closeness.

Research is increasingly focusing on the use of micronutrients in the treatment of

psychiatric disorders. Cooper, Tye, Kuntsi, Vassos and Asherson (2015) conducted a

systematic review of 10 meta -analyses and found that higher quality studies with strict

inclusion criteria showed that taking omega- 3 polyunsaturated fatty acid supplementation

significantly reduced symptoms of emotional lability and oppositional behaviour in children

with ADHD. However, Benton (2003) argues that the multi- micronutrient approach may be

best since nutrients do not function in isolation. Kaplan, Fisher, Crawford, Field and Kolb

(2004) found that children clinically diagnosed with an anxiety, mood or behavioural

disorders benefited from a micronutrient treatment over two to more than four months in

an open – label trial. The standardized mean difference effect sizes for mood and anxiety

symptoms improvement were both around 0.80 based on pre and post-test measures.


Protocol for micronutrients and traumatic brain injury: a feasibility study NZResearch has also found that micronutrients are essential for the development of a healthy

brain. When comparing micronutrient intervention versus placebo, researchers found

children with an ADHD diagnosis assigned to the micronutrient group reported improved

emotional dysregulation (ES= 0.51) and global functioning (ES= 0.48), and reduced

aggression and dysregulated mood with effect sizes between 0.35 and 0.66. As noted above,

studies on short- and long-term outcomes of TBI in children have helped determine that

little improvement occurs a year after injury. Therefore, managing co-morbid conditions

using micronutrients might improve outcomes. A recent single case study showed the

benefits of a micronutrient formula on emotional dyscontrol even eight years after a TBI

(Kaplan, Leaney and Tsatsko, 2016). In this case study, the researchers used the same

micronutrient formula as the one proposed for this current study.

Finally, research shows that behavioural adjustment and academic performance in

individuals with TBI are better predicted by injury severity and environmental factors such

as parenting circumstances and family environment (Yeates et al., 1997; Yeates et al., 2002).

A longitudinal study by Taylor et al. (2000) found a bidirectional relationship between

children’s behaviour and parent psychological burden during the first twelve months post

injury. They argue that positive parent- child interactions is likely to result in reduced child

behaviour problems and vice versa. However, Garcia, Siegel and Bass (1992) did not find

such effect. Understanding whether an interaction exists between emotional regulation

improvement in children and parenting is likely to contribute to this field of research. To the

best of our knowledge, no such research has been undertaken before.

Aims and ObjectivesThe proposed research is a feasibility study investigating whether children with a Traumatic

Brain Injury are able to adhere to a six months intervention of broad-spectrum

micronutrient formula, to assess the safety and tolerability of a specific formulation, Daily

Essential Nutrients and to observe if there are any changes in the children’s ability to

manage their emotions. The study is also interested in understanding the impact the

intervention might have on parental stress. The study also aims to understand whether

individual comorbid symptoms, determined during an initial interview with participants and


Protocol for micronutrients and traumatic brain injury: a feasibility study NZfamilies, vary during the intervention. Based on previous research, we expect those

symptoms to be low mood, anxiety, sleep disturbances and ADHD.

Method

Study design

This series of individual cases will consist of three study periods:

Baseline assessment: two baseline assessments over two weeks will be conducted.

Intervention phase: a 6-month intervention for all participants using a well-researched

micronutrient formula.

Follow up: participants will be followed up naturalistically at 9 months post baseline.

Participant recruitment and the referral process:All participants will be recruited with the help of ACC. We have secured approval from ACC

to conduct this research as long as it is ethically approved. We have confirmed there is a

sample that meet our inclusion criteria who could be invited to participate. Case managers

who are already working with the participants and their families will explain what the study

is about and offer to contact the research team directly if interested. ACC case managers

will only be involved in introducing the study to the participants. In no other way will they

be involved. They will inform families of the study and provide them with a study flyer.

Families interested in finding out more or participating will be required to contact the

research team themselves. Participation in this study will not affect the ACC claim.

Baseline Assessment: Demographic information will also be collected including ethnicity, occupation, level of

education of the parents and psychiatric family history. The SES of each participant will be

estimated using the New Zealand Socioeconomic Index of Occupational Status (NZSEI). This

will allow us to have a detailed description of the challenges the child faces prior to

commencement in the study.

During this baseline interview, questionnaires will also be administered to assess baseline

symptoms for the children and their parents. For full details of the measures to be used,


Protocol for micronutrients and traumatic brain injury: a feasibility study NZplease see the section “Assessment Tools” below. This information will determine what

individualised measures will be used with each participant through the study. Some of these

assessments will be repeated two weeks later to ensure consistent baseline measures and

identify any potential regression to the mean effects.

Participants will be asked to provide blood samples and the following baseline biomarkers

will be gathered: haematological and biochemistry variables, including liver function tests

(GGT; AST; ALT), iron studies and plasma copper. Results will be provided to the

participant’s GP (with consent). All lab results will be reviewed by our study physician (Dr

Matthew Eggleston) prior to beginning the trial. In cases where our clinician identifies any

issues with a participant taking part in this study based on their blood test results, our study

physician will discuss this with the participant’s GP. Participants identified as having trouble

swallowing pills will be asked to complete the pill swallowing programme developed by

Kaplan et al, 2010. The video can be viewed at:

http://research4kids.ucalgary.ca/pillswallowing. If the participant continues to struggle with

swallowing the capsules after the training, the formula is available in powdered form that

could be incorporated into a smoothie or milkshake to be taken at the same dose and rate

as the capsules. Participants can also choose a combination of the powder and capsules.

Inclusion Criteria: 1) Between 6 and 13 years, 2) must be children or young people with a Traumatic Brain

Injury more than a year old, and 3) meet the criteria for emotional dysregulation as defined

by the Affective Reactivity Scale. Participants will be assessed on the ARI- P (parent scale).

Those scoring more than 3 will be considered eligible.

Exclusion criteria: 1) A known allergy to any of the ingredient used in the intervention, 2) any known

abnormality of mineral metabolism (e.g., Wilson's disease, haemochromatosis – assessed

via blood tests), 3) ingestion of any medications with primarily central nervous system

activity, including mood stabilizers, atomoxetine or stimulants. Participants must have been

off their medications for a minimum of four weeks prior to the trial. Participants will not be

encouraged to come off their medications in order to participate.

Titration and dosing: We will be using a formulation called Daily Essential Nutrients (DEN) which consists of a

blend of vitamins, minerals, amino acids and antioxidants (see Appendix A for ingredients of


http://research4kids.ucalgary.ca/pillswallowing

Protocol for micronutrients and traumatic brain injury: a feasibility study NZDEN). Participants will begin by taking one capsules three times per day, increasing the dose

by three capsules every two days up to a target dose of 9 capsules per day: three taken at

three different intervals (or the equivalent in powder form). Some participants may need to

increase the dose more slowly. If there has been no improvement after 4 weeks, a further

dose increase will be discussed with the families up to a maximum of 12 per day (four three

times a day). Participants will be monitored monthly, for a total of 6 visits, and asked a

range of questions about physical and mental functioning (see measures below). Capsules

will be dispensed at each assessment and participants will be asked to monitor compliance

with taking the capsules. At each visit they will also be asked about any adverse events. At

the completion of the 6 months intervention phase, participants will be re-assessed using

the same baseline measures. The DEN capsules/powder will be donated for the 6-month

study duration by Hardy Nutritionals.

Assessment Tools1. The Affective Reactivity Index (ARI) will be used as a baseline screening tool in

combination with a semi structured interview. The scale contains 6 items related to

feelings and behaviours specific to irritability and 1 item related to impairment that is

counted separately. Each item is scored on a 3 -level response: ‘not true’, ‘somewhat

true’ and ‘certainly not true’ translated into 0, 1, 2 scores. Both parent and self-

report scales are composed with identical items.

Clinician-rated measures (completed at both baseline and every monthly visit – time: 45 minutes):

1. Overt Behaviour Scale – Kids adapted specifically to this study. The scale contains 9

categories of behaviour but only the one relevant to this study will be used. Those

categories are: verbal aggression, physical aggression, perseveration/ repetitive

behaviour, wandering/ absconding and lack of initiation. This scale will be

administered at the beginning and the end of the intervention as well as at the

follow up visit.

2. Clinical Global Impressions Scale (CGI) The CGI is a single-item rating of the clinician’s

assessment of the severity of symptoms and response to intervention. Its goal is to

allow the clinician to rate the efficacy of treatment and the severity of illness.


Protocol for micronutrients and traumatic brain injury: a feasibility study NZDepending on the presenting problems, the CGI will be modified to assess affective

dysregulation, mood, anger, anxiety and global function.

3. ADHD Rating Scale IV – (ADHD –RS) – clinician version, parent version, an 18-item

scale with one item for each of the 18 symptoms contained in the DSM-IV diagnosis

of ADHD. Each item is scored on a 0 to 3 scale: 0 = none (never or rarely); 1 = mild

(sometimes); 2 = moderate (often); 3 = severe (very often).

Parent- rated measures (completed at appropriate times during trial – total time: 45 minutes or less):

1. Strengths and Difficulties Questionnaire (SDQ) is used to assess child mental health

problems and is suitable for parents and teachers to use. It assesses positive and

negative psychological attributes measuring both problem behaviours and

competencies at an early age.

2. The Behavior Rating Inventory of Executive Function (BRIEF) is a behavioural rating

measure that was specifically designed to assess child and adolescent everyday

executive skills in natural, everyday environments, including home and school. The

BRIEF is composed of two major index scales and a composite of the two, which are

the Behavioral Regulation Index (BRI), the Metacognition Index (MI), and the Global

Executive Composite (GEC). Each of the two major index scales is further composed

of scales. There are Eight clinical scales (Inhibit, Shift, Emotional Control, Initiate,

Working Memory, Plan/Organize, Organization of Materials, Monitor) and two

validity scales (Inconsistency and Negativity). The BRI is composed of the Inhibit,

Shift, and Emotional Control scales, and the MI is composed of the Initiate, Working

Memory, Plan/Organize, Organization of Materials, and Monitor scales. It takes 15

minutes to administer. It is completed by parents.

3. The parent stress index (PSI) is a self-reported measure of stress directly associated

with parenting such as parental distress, parent-child dysfunction and child

characteristics. The measure contains 120 statements. Participants respond on a 5-

point scale from Strongly Agree to Strongly Disagree.

4. EATING BEHAVIOURS at baseline: a brief diet intake questionnaire (modified from

Baker, Little, and Brownell (2003)) to assess the child’s dietary patterns, including

consumption of fruit and vegetables.



Child-rated measures - (every visit – time: 15 minutes)1. Measure Yourself Medical Outcome Profile (MYMOP): a self-report outcome

questionnaire about symptoms, side-effects and well-being. This questionnaire

shows construct validity and sensitivity to change. Parents will also be interviewed

on side effects.

2. Side-effects questionnaire: developed for this study and used with children, this

measure asks the participant to rate any physical side effects they may have

experienced in the last two weeks, which they attribute to taking the capsules.

3. Pill taking measure: this brief measure asks the child to rate his/her adherence to

taking the capsules since the last visit. Any problems with swallowing the capsules or

remembering to take them are identified and discussed.

Blood testing (baseline – time: 45 minutes): Participants will provide a blood sample (20ml, ~ 4 teaspoons) at the start, before taking any

pills, to assess for any metabolic disorders and to ensure that all systems are functioning

normally. These samples will provide us with haematological and biochemistry screening,

full blood count; liver function tests (GGT; AST; ALT), iron studies and plasma copper. While

risks associated with blood tests are usually minimal, bruising can occur with blood tests.

The results of laboratory testing will need to be sent to us with a copy to the child’s general

practitioner such that they can be reviewed accordingly. The purpose of the blood testing is

to ensure there are no metabolic issues (like poor copper metabolism) that may preclude

the child from participating.

Statistical Analysis

All statistical analyses will be carried out using the Statistical Package for Social Science

(SPSS), Excel and Sigma Plot. This study’s data analysis will be predominantly a descriptive

time series of the various Dependent Variables measured such as emotional dysregulation

and ADHD.

The researchers will undertake two baseline measures two weeks apart to establish stability

in the various core dependent variables and observe any regression to the mean effects.

Modified Brinley Plots will be used to visually track changes over time relative to baseline.



Anticipated costs

Participant reimbursement: Participants/families will be given a 10 dollar petrol voucher to

cover travel costs for every visit to the University.

Pill organiser: Each participant will be provided with a pill organiser to assist with

compliance. Cost per participant: NZ$15. Funding for pill organisers will be covered by the

University of Canterbury.

ResourcesStudy formulas and capsules packaging will be donated by Hardy Nutritionals, Canada.

Professor Julia Rucklidge has received generous philanthropic donations to support her

research and these funds can be used for blood tests, pharmacy costs and participant

reimbursement.

TimetableDate Event

August 2019 Begin recruiting participants

September 2019 Access to participant notes

Intervention starts

May 2020 Intervention ends

August 2020 Follow up

EthicsThe overall safety of all involved in of the outmost importance. The following safety protocol

outlines what safety measures have been put in place to ensure safety of researchers and

participants at the University. Appointments with participants and consenting parents will

be scheduled over the phone.



Safety protocol related to visits at the University Lab:The University of Canterbury has very clear Health and Safety procedures for all visitors. We

have a dedicated Health and Safety Team at the University:

https://www.canterbury.ac.nz/about/health-and-safety/. The Lab is situated within a large

School of Psychology, Speech and Hearing. All students and staff are trained to deal with

emergency situations, such as evacuations, fire, and earthquakes. The Director of the

Mental Health and Nutrition Lab is a First Aid holder and we are equipped with a First Aid

Kit. All short term visitors are briefed as to the Emergency evacuation procedures. All staff

and students who work with individuals under the age of 18 obtain a police check. The

Director of the lab and one of the current PhD students are registered clinical psychologists

such that in the event of any concerns for the wellbeing of participants, we have on hand

trained professionals capable of dealing with such circumstances that may arise. In addition,

within 20 meters of the lab there are a further 6 registered psychologists available for

consultation should the need arise.

Participant safety is the most important concern. All participants will be recruited through

case managers contacts at ACC and informed of the best intervention standard for

emotional dysregulation and other comorbid symptoms such as depression and anxiety

prior to enrolment. Participants will be screened to ensure that there are no physical or

metabolic (e.g. Wilson’s disease) conditions that may preclude participation. This clearance

will be conducted by the study physician.

Children may be discontinued from the study if they show adverse symptoms of either a

physical or psychological nature, in response to the micronutrients. We will continually

monitor for adverse symptoms. If the child experiences an increase in symptoms the

consenting parent must contact the study investigators who in discussion with them, as the

consenting party, may refer the child to their GP or psychiatric emergency services. If the

child’s psychological state deteriorates to a clinically significant degree during the trial, the

investigators will discuss with the consenting parent the possibility of withdrawing from the

study, or may decide that the child should be withdrawn. If withdrawn, we will refer the

child to their GP or emergency services as appropriate. The consenting parent to this study,

may also request their child to be withdrawn from the study or withdraw consent at any “Micronutrients and TBI in children: a feasibility study;” June 2019; UTN: U1111-1230-3860; SHDEC

19/STH/68 14 | P a g e

https://www.canterbury.ac.nz/about/health-and-safety/

Protocol for micronutrients and traumatic brain injury: a feasibility study NZtime without penalty. In the event of a physical or psychiatric emergency, the consenting

parent is advised to contact emergency services or visit the emergency department

immediately.

If a participant, for any reason, requires treatment with certain therapeutic agents (i.e.

antibiotics), we note what they are taking and for how long. If a protocol exclusion violation

has occurred (i.e., participant requires psychiatric medications), the participant’s

involvement will be discontinued. If any participant is discontinued from the trial or decides

to withdraw, we will carry out follow-ups to ensure participant well-being.

Data were assembled from all known published and unpublished studies of the

micronutrient product used in the study (Simpson, et al, 2011), which boasts the largest

amount of published research in the mental health field for a complex micronutrient

product. Biological safety data from 144 children and adults, available from six sources,

revealed no occurrences of clinically meaningful negative outcomes/effects. Further, no

abnormal blood tests could be attributed to toxicity. Adverse event information from 157

children and adults showed only minor, transitory reports of headache and nausea. In

general, comparing tolerability data between micronutrient group and those taking

medication, those in the micronutrient group reported significantly fewer adverse events

and less weight gain than participants treated with medication.

In an RCT conducted at University of Canterbury with adults (Rucklidge et al, 2014), the only

recurring side effect of the formula was the aforementioned transitory gastrointestinal

difficulties (loose stool, nausea or vomiting, if the product was taken on an empty stomach,

contrary to recommendation) although this side effect did not occur more frequently in the

active group as compared with the placebo group. In a couple of studies conducted with

children (Sole, Rucklidge & Blampied, 2017, Rucklidge et al., 2018), sleep initiation, nausea

and agitation were reported as an adverse effect; however, this was overcome by taking the

pills at least 2 hours before going to bed or reducing the dosage then building it back to the

necessary dosage over 4 to 5 weeks were enough to alleviate those side effects. These

difficulties can be avoided or reduced by taking the capsules on a full stomach, and so we


Protocol for micronutrients and traumatic brain injury: a feasibility study NZsuggest participants always take their capsules with food. Another way to prevent these side

effects is to increase the dose slowly over several days, so participants begin with three

capsules per day and increase gradually to the full dose of 9 capsules per day.

We have consulted with the Māori Research Advisory Group at the University of Canterbury

regarding this type of research and the study has received approval to conduct nutritional

research with Māori. The group is available for further consultation throughout the project.

Furthermore, the primary investigator has been actively involved in developing cultural

awareness including taking Te reo Māori, attending Hui at Nga Tauira Hinengaro, Te

Wananga O Otautahi, Ngati Moki marae, attending Treaty of Waitangi workshops and

maintaining on-going cultural competency as part of registration as a clinical psychologist

with the New Zealand Psychologist’s Board. Should any participants identify as Māori, they

will be asked if they would like a Pukenga Atawhai or other support person to attend the

assessments as well as whether there are other members of their whanau whom they

would like to have present during the study.

Research site Mental Health and Nutrition Laboratory; Room 465

Department of Psychology

University of Canterbury

Private Bag 4800

Christchurch 8140

New Zealand

InvestigatorsProf Julia Rucklidge: Primary investigator. Prof Rucklidge will oversee the running of the

study and provide support and supervision to researchers on the project, being available at

all times should any difficulties arise.

Dr Matthew Eggleston: Study physician. Dr Eggleston will approve participants’ enrolment in

the trial; will oversee the safety of the blood work and address clinical issues/adverse events

as they arise.


Protocol for micronutrients and traumatic brain injury: a feasibility study NZProf Neville Blampied: Co- Investigator. Prof Blampied will provide support and supervision

to researchers on the project with specific expertise in case study design.

Amanda Wallwork: psychologist. Amanda Wallwork will provide support and supervision to

researchers on the project and ACC support.

Dr Audrey McKinley. Dr McKinlay will assist with her expertise on Traumatic Brain Injury.

Sophie Waretini: Research co-ordinator and Master student. Sophie will assist in the daily

administration of the trial including assessments with participants and providing the study

intervention. This project will serve as Sophie’s Master’s thesis qualification.

Risk Management As the principal investigator and as someone located on site for data collection, the

responsibility for risk management (such as managing psychological symptoms) of the

project will be undertaken by Prof Rucklidge (registered clinical psychologist) in consultation

with Dr Eggleston (child psychiatrist). Any reported adverse effects will be discussed with Dr

Eggleston who will determine whether further investigation is required. Prof. Rucklidge will

be consulted on all aspects of the project and will therefore be aware of any foreseeable

risks which can then be reviewed and cleared with the study physician. Any serious adverse

effects will be reported to the ethics committees (HDEC and Human Ethics Committee at

University of Canterbury). The trial will be terminated if serious adverse effects known to be

caused by the nutrients occur.

Data ownershipAll data associated with the study and all reports resulting from the same will be owned by

the authors.

Conflicts of interestThere is no conflict of interest in the proposed study. The supplements used in this trial will

be donated by the manufacturers. Study investigators have no financial affiliations with the

manufacturer of the product.



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Appendices

Appendix A: Daily Essential Nutrients ingredient list

Ingredients: 1 capsule 12 capsules

Vitamin A (as retinyl palmitate) 480 IU 5,760 IU

Vitamin C (as ascorbic acid) 50 mg 600 mg

Vitamin D (as cholecalciferol) 250 IU 3,000 IU

Vitamin E (as d-alpha tocopheryl succinate) 30 IU 360 IU

Vitamin K (75% as phylloquinone; 25% as menaquinone-7) 10 mcg 120 mcg

Thiamin (as thiamin mononitrate) 4 mg 60 mg

Riboflavin 1.5 mg 18 mg

Niacin (as niacinamide) 7.5 mg 90 mg

Vitamin B6 (as pyridoxine hydrochloride) 5.8 mg 69.9 mg

Folate (as L-methylfolate calcium) 66.8 mcg 801 mcg

Vitamin B12 (as methylcobalamin) 75 mcg 900 mcg

Biotin 90 mcg 1080 mcg

Pantothenic acid (as d-calcium pantothenate) 2.5 mg 30 mg

Calcium (as chelate) 110 mg 1,320 mg

Iron (as chelate) 1.15 mg 13.8 mg

Phosphorus (as chelate) 70 mg 840 mg

Iodine (as chelate) 17 mcg 204 mcg

Magnesium (as chelate) 50 mg 600 mg

Zinc (as chelate) 4 mg 48 mg

Selenium (as chelate) 17 mcg 204 mcg

Copper (as chelate) 0.6 mg 7.2 mg

Manganese (as chelate) 0.8 mg 9.6 mg

Chromium (as chelate) 52 mcg 624 mcg

Molybdenum (as chelate) 12 mcg 144 mcg

Potassium (as chelate) 20 mg 240 mg


Protocol for micronutrients and traumatic brain injury: a feasibility study NZProprietary blend ingredients: 1 capsule 12 capsules

Choline bitartrate 45 mg 450 mg

Alpha-lipoic acid 41.6 mg 500 mg

Mineral wax 28.1 mg 337.5 mg

Inositol 15 mg 180 mg

Acetylcarnitine (as acetyl-L-carnitine hydrochloride) 5 mg 60 mg

Grape seed extract 3.7 mg 45 mg

Ginkgo biloba leaf extract 3 mg 36 mg

Methionine (as L-methionine hydrochloride) 2.5 mg 30 mg

Cysteine (as N-acetyl-L-cysteine) 2.5 mg 30 mg

Boron (as chelate) 0.2 mg 2.4 mg

Vanadium (as chelate) 0.09 mg 1.19 mg

Lithium orotate (as chelate) 0.08 mg 1 mg

Nickel (as chelate) 0.002 mg 0.03 mg



Appendix C: Schedule of EventsBase-line

Base-Line 2

Wk 2 Mth 1 Mth 2 Mth 3 Mth 4 Mth 5 Mth 6 Mth 12

Screening:

ARI X X X X X X X X X X

Scales:

CLINICIAN

CGI X X X X X X X X X X

OBS – Kids X X X

PARENT

SDQ X X X X X X X X X X

ADHD-RS-IV X X X X X X X X X X

BRIEF X X X

Adverse Events

X X X X X X X X X X

PSI X X X X

Side Effects X X X X X X X X X XCHILD

MYMOP adaptation

X X X X X X X X X X

Side Effects /adverse events

X X X X X X X X X X

Pill Taking X X X X X X X X

Blood X


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